Vascular endothelial growth factor (VEGF) signaling is a critical regulator of vasculogenesis, angiogenesis, and lymphangiogenesis, processes that are vital for the development of vascular and lymphatic systems, tissue repair, and the maintenance of homeostasis. VEGF ligands and their receptors orchestrate endothelial cell proliferation, migration, and survival, playing a pivotal role in dynamic vascular remodeling. Dysregulated VEGF signaling drives diverse pathological conditions, including tumor angiogenesis, cardiovascular diseases, and ocular disorders. Excessive VEGF activity promotes tumor growth, invasion, and metastasis, while insufficient signaling contributes to impaired wound healing and ischemic diseases. VEGF-targeted therapies, such as monoclonal antibodies and tyrosine kinase inhibitors, have revolutionized the treatment of diseases involving pathological angiogenesis, offering significant clinical benefits in oncology and ophthalmology. These therapies inhibit angiogenesis and slow disease progression, but they often face challenges such as therapeutic resistance, suboptimal efficacy, and adverse effects. To further explore these issues, this review provides a comprehensive overview of VEGF ligands and receptors, elucidating their molecular mechanisms and regulatory networks. It evaluates the latest progress in VEGF-targeted therapies and examines strategies to address current challenges, such as resistance mechanisms. Moreover, the discussion includes emerging therapeutic strategies such as innovative drug delivery systems and combination therapies, highlighting the continuous efforts to improve the effectiveness and safety of VEGF-targeted treatments. This review highlights the translational potential of recent discoveries in VEGF biology for improving patient outcomes.

Current developments in bioequivalent technology have led to the creation of excellent models that mimic the structure and function of human organs. These models are based on the original tissues and organs of the human body, but they lack the complex interaction with the extensive network of vasculature, and this is a major challenge for these models. A functional vasculature is essential for oxygen, nutrient, and waste exchange. It is also responsible for inductive biochemical exchange, and provides a structural pattern for organ growth. In vitro systems, containing no perfusable vessels, suffer from the quick formation of a necrotic core of organoids, and further development does not occur due to increased metabolic demands. Another key limitation of 3D-based techniques is the absence of accurate architectural structures and large-scale tissue sizes. Recently, new 3D bioprinting methods have been developed for organoids and spheroids as living building blocks. These methods aim to address some of the challenges associated with 3D technologies. In this review, we discuss recent strategies for vascularization via organoids and spheroids, which are used as structural units in bioprinting to recreate natural organs and tissues with ever-increasing accuracy in structure and function.

Fat grafting is widely utilized in reconstructive and esthetic plastic surgery, typically with minimal complications. Nevertheless, the occurrence of fat necrosis is dependent on the technique used for fat extraction, tissue processing and the volume of the graft. The longevity of the graft critically depends on the presence of adipose-derived stromal cells (ADSC) and their promotion of a reconstituted vascular supply.

This study seeks to determine whether there are differences in 13 angiogenesis-related adipokines based on their grouping by vascular endothelial growth factor (VEGF) expression levels.

The expression of 14 adipokines related to angiogenesis in 12 cultured ADSCs was evaluated using Human Adipokine Profiler kits, which simultaneously detect 58 mediators. Adipokines of the high and low VEGF expression groups were evaluated for their expression of the remaining 13 angiogenic proteins.

We were able to show that there are significant differences in VEGFlow and VEGFhigh ADSCs regarding fibroblast growth factor 19 (p = 0.043) and insulin like growth factor binding protein 3 (p = 0.028). Furthermore, ADSCs with differentially highly expressed VEGF show a different pattern in the amount of protein levels regarding the 13 other adipokines observed.

The VEGF has been described as a key angiogenic factor in fat grafts that may be linked to successful grafting; however, two of the fat samples analyzed exhibited high expression of VEGF but lacked significant co-expression of a range of other angiogenic factors. Thus, the assessment of the expression of predisposing mediators for graft angiogenesis for wound healing or contouring should include further angiogenesis promoters aside VEGF as parameters.

During uterine spiral artery remodeling, vascular smooth muscle cells (VSMCs) become disorganized and undergo phenotypic switching from a contractile to a more synthetic phenotype. We have previously reported that uterine natural killer cells induce this VSMC phenotypic switching by secreting angiopoietin-2 (Ang-2). Here, we identified the specific mechanisms by which Ang-2 plays a role in this phenomenon. VSMCs isolated from human umbilical arteries were used as an in vitro model to investigate the role of Ang-2 in phenotypic switching. Human decidua tissue from preeclamptic and control pregnancies was collected to compare the expression levels of related proteins. Ang-2 induced a more synthetic phenotype in VSMCs as evidenced by decreased contractile marker expression, increased proliferation and migration, and an altered cytoskeleton. VSMC expressed integrin β6 interacted directly with Ang-2 and induced phosphorylation of FAK (S910 and Y397), AKT (S473), and mTOR (S2448). Knockdown of FAK recovered the calponin loss induced by Ang-2 and resulted in lower EZH2 abundance. Inhibition of FAK and EZH2 both attenuated Ang-2-induced inhibition of the LC3 II/LC3 I ratio and ATG7 expression, and proliferation. Lipid peroxidation inhibition by ferrostatin-1 or the IL-8 receptor antagonist navarixin inhibited the Ang-2-induced migration. IL-8 secretion was significantly lower with lipid peroxidation inhibition. In preeclamptic decidua, there were more unremodeled spiral arteries, and the abundance of Ang-2 was dysregulated. Ang-2 dysregulation may disrupt spiral artery remodeling and contribute to preeclampsia. Ang-2 may be a novel therapeutic target for the treatment of pregnancy complications affected by incomplete spiral artery remodeling.

Bleeding in the gastrointestinal tract in patients with von Willebrand disease continues to pose a therapeutic challenge for clinicians. It is associated with significant morbidity and mortality and represents the major unmet need in this disease. Defective angiogenesis in the gut is primarily responsible, resulting in angiodysplastic malformations making bleeding notoriously refractory to standard replacement therapy. A substantial body of evidence now shows that von Willebrand factor has a role in the regulation of angiogenesis but the mechanisms responsible for the formation of vascular malformations remain incompletely understood. Data from the wider field of vascular malformations may lend insight and point to novel therapeutic approaches. Here we review evidence linking von Willebrand factor to angiodysplasia, the associated molecular mechanisms and the implications for therapy.

Background and Objectives: Age-related macular degeneration (AMD) remains a leading cause of legal blindness. Anti-Vascular Endothelial Growth Factor (VEGF) agents are the first-line treatment for neovascular AMD (nAMD). The choroid plays a key role in AMD and is affected by the anti-VEGF treatment. Faricimab, a bispecific antibody additionally targeting angiopoietin 2 (Ang2), was recently approved for nAMD treatment. This study investigates the effect of Faricimab on choroidal flow signal. Materials and Methods: Optical coherence tomography angiography images of 29 nAMD eyes were examined retrospectively. Patients had received treatment with other anti-VEGF agents before Faricimab application. The flow signal in the choroid was measured before, after one and after a series of ≥2 Faricimab injections. Results: The flow signal decreased significantly (p = 0.026) at the choriocapillaris (CC) level after ≥2 injections. The flow signal did not show a significant change in Haller's layer but increased slightly in Sattler's layer (p = 0.034). Conclusions: In conclusion, our results show that the flow signal, especially at the CC level, changed during treatment. Despite the known influence of anti-VEGF treatment on the choroid, auxiliary inhibition of Ang2 might enhance this effect. Due to the retrospective nature, moderate sample size and non-treatment, naïve patients, care must be taken while interpreting our observations. Prospective studies with larger sample sizes and treatment-naïve patients will be needed.

It is becoming increasingly evident that diabetic vascular complications seriously threaten human health. The most prevalent microvascular complications include kidney disease, retinal disease, cardiovascular diseases and amputation. Conventional treatments can only relieve the progression of the diseases, and is no longer appropriate for the long-term management of diabetic patients. Exploring a novel therapeutic regimens and improvements in management of Diabetic Complications is required. Alternative splicing has been found to play a crucial role in the occurrence and treatment of diseases, including the destruction and generation of blood vessels in diabetes. Alternative splicing is an important factor in the high complexity of multicellular eukaryotic transcriptome, and angiogenesis, which is an important process controlled by alternative splicing mechanism. This review mainly introduces the current understanding of alternative splicing and the role that alternative splicing plays in the diabetic complications, with a special focus on vascular system. In this study, we summarized alternative splicing in relation to diabetes complications and the pathogenesis of diabetic vasculopathy. It discussed potential treatment strategies for correcting aberrant splicing and suggested novel approaches for addressing diabetes complications.

Ischemia and hypoxia caused by vascular injury intensify nerve damage. Skin precursor-derived Schwann cells have demonstrated an accelerated in vivo prevascularization of tissue-engineered nerves. Furthermore, extracellular vesicles from skin precursor-derived Schwann cells (SKP-SC-EVs) show the potential in aiding peripheral nerve regeneration. Nonetheless, the capacity of SKP-SC-EVs to facilitate nerve repair via angiogenesis remains uncertain. This study observed that SKP-SC-EVs significantly enhanced angiogenesis, evidenced by increased transparency of the tissue-engineered nerve graft and ultrasonic blood flow imaging. In vitro experiments confirmed that SKP-SC-EVs promote the proliferation, migration, and tube formation of human umbilical vein endothelial cells, a standard model for assessing angiogenic potential. Additionally, a comprehensive miRNA expression profile of SKP-SC-EVs was performed, leading to the identification of potential candidates through functional experiments. Among these, miR-30a-5p emerged as a significant candidate, demonstrating remarkable proangiogenic effects both in vivo and in vitro, akin to the effects of SKP-SC-EVs. Furthermore, luciferase reporter assay and functional experiments revealed that miR-30a-5p in SKP-SC-EVs promotes angiogenesis by targeting ANGPT2 and LIF without sufficient VEGFa. Thus, the enrichment of miR-30a-5p in SKP-SC-EVs indicates its pivotal role as a regulator of angiogenesis, presenting a promising avenue for cell-free treatment of peripheral nerve injury.

Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder caused by mutations in the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. While previously thought to share molecular and cellular dysregulation, this study reveals highly distinct mechanisms depending on whether mutations occur in Alk1 or SMAD4. Loss of SMAD4 enhances endothelial cell responses to flow, including flow-regulated transcription and cell migration against blood flow, causing excessive pruning of capillaries and the formation of single large shunts. Conversely, Alk1 deficiency disrupts endothelial flow responses, including cell polarization and directional migration, leading to a dense vascular network and the persistence of a malformation nidus. In vivo cell population tracking of mutant cells validates unique endothelial cell migration defects. Mosaic cell culture models further illustrate that mutant cells co-opt wild-type cells driving distinct Alk1 or SMAD4 mutant-like behavioral defects. These findings demonstrate that arteriovenous malformations develop through fundamentally different cellular mechanisms based on the specific genetic mutation emphasizing the need for tailored diagnostic and therapeutic strategies.

Angiopoietin-2, an important contributor to angiogenesis and vascular remodeling, is increasingly recognized in kidney research. This review explores clinical insights and experimental perspectives on angiopoietin-2 in kidney diseases. Traditionally seen as an antagonist of the Tie-2, which is a receptor tyrosine kinase of endothelial cells and some hematopoietic stem cells, angiopoietin-2 exerts both proangiogenic and antiangiogenic effects, making it a versatile and context-dependent player in kidney pathophysiology. Elevated circulating angiopoietin-2 levels in clinical scenarios are associated with sepsis and acute kidney injury (AKI), emphasizing its role as a biomarker of disease severity. In diabetic kidney disease, circulating angiopoietin-2 correlates with albuminuria, a crucial indicator of disease progression, and may serve as a treatment target in protecting the endothelium. Angiopoietin-2 is implicated in chronic kidney diseases (CKDs), where its elevated circulating levels correlate with kidney outcomes and cardiovascular complications, suggesting its potential impact on kidney function and overall health. In experimental settings, angiopoietin-2 plays a pivotal role in angiogenesis and lymphangiogenesis, influencing vascular stability and endothelial integrity. The context-dependent agonist and antagonist role of angiopoietin-2 is regulated by a Tie-2 phosphatase, vascular endothelial protein tyrosine phosphatase (VEPTP), further underscoring its complexity. Angiopoietin-2 is also involved in regulating cellular integrity, inflammation, and endothelial permeability, making it a promising therapeutic target for conditions characterized by disrupted endothelial junctions and vascular dysfunction. This review provides a comprehensive overview of the diverse roles of angiopoietin-2 in kidney research, offering insights into potential therapeutic targets and advancements in managing kidney diseases.

Pericytes are vascular mural cells that support the microvasculature; their dysfunction contributes to diabetic retinopathy and has been linked to obesity in humans. To explore the role of pericyte insulin signalling on systemic metabolism we utilised male mice from our previously described PIR-/- (PIRKO) mouse line which has insulin receptor (Insr) knockout in PDGFRβ-expressing cells. These animals exhibit systemic insulin resistance from as early as 8-weeks of age, despite no change in body weight or activity level, and show altered body composition and hepatosteatosis. When challenged with high fat diet, PIR-/- remain insulin resistant but are protected from weight gain with reduced adipose tissue expansion across all depots and altered adipose morphology. Exhibiting parallels with the metabolically-obese-normal-weight (MONW) human phenotype, the PIR-/- line underlines the importance of pericyte biology in the development of both diabetes and obesity and establishes the angiopoietin (Ang)/Tie signalling pathway as a focus for future research.

In recent years, the chorioallantoic membrane (CAM) has emerged as a crucial component of biocompatibility testing for biomaterials designed for regenerative strategies and tissue engineering applications. This study explores angiogenic potential of an innovative acellular and porous biopolymer scaffold, based on polyhydroxybutyrate and chitosan (PHB/CHIT), using the ex ovo quail CAM assay as an alternative to the conventional chick CAM test. On embryonic day 6 (ED6), we placed the tested biomaterials on the CAM alone or soaked them with various substances, including vascular endothelial growth factor (VEGF-A), saline, or the endogenous angiogenesis inhibitor Angiostatin. After 72 h (ED9), we analyzed blood vessels formation, a sign of ongoing angiogenesis, in the vicinity of the scaffold and within its pores. We employed marker for cell proliferation (PHH3), embryonic endothelium (WGA, SNA), myofibroblasts (α-SMA), and endothelial cells (QH1) for morphological and histochemical analysis. Our findings demonstrated the robust angiogenic potential of the untreated scaffold without additional influence from the angiogenic factor VEGF-A. Furthermore, gene expression analysis revealed an upregulation of pro-angiogenic growth factors, including VEGF-A, ANG-2, and VE-Cadherin after 5 days of implantation, indicative of a pro-angiogenic microenvironment. These results underscore the inherent angiogenic potential of the PHB/CHIT composite. Additionally, monitoring of CAM microvilli growing to the scaffold provides a methodology for investigating the biocompatibility of materials using the ex ovo quail CAM assay as a suitable alternative model compared to the chicken CAM platform. This approach offers a rapid screening method for biomaterials in the field of tissue repair/regeneration and engineering.

Cancer remains one of the leading causes of death worldwide and poses a significant challenge to effective treatment due to its complexity. Angiogenesis, the formation of new blood vessels, is one of the cancer hallmarks and is a critical process in tumor growth and metastasis. The pivotal role of angiogenesis in cancer development has made antiangiogenic treatment a promising strategy for cancer therapy. To develop an effective therapy, it is essential to understand the basics of the physiological and tumor angiogenesis process. This review presents the primary factors related to physiological and tumor angiogenesis and the mechanisms of angiogenesis in tumors. We summarize potential molecular targets for cancer treatment by focusing on the vasculature, with the VEGF/VEGFR pathway being one of the most important and well-studied. Additionally, we present the advantages and limitations of currently used clinical protocols for cancer treatment targeting the VEGF/VEGFR pathway.

Secretogranin III (Scg3) is a diabetic retinopathy (DR)-restricted angiogenic factor identified in preclinical studies as a target for DR therapy. Previously, our group generated and characterized ML49.3, an anti-Scg3 monoclonal antibody (mAb) which we then converted into an EBP2 humanized antibody Fab fragment (hFab) with potential for clinical application. We also generated anti-Scg3 mT4 mAb and related EBP3 hFab. In this study, to identify the preferred hFab for DR therapy, we compared all four antibodies for binding, neutralizing and therapeutic activities in vitro and in vivo. Octet binding kinetics analyses revealed that ML49.3 mAb, EBP2 hFab, mT4 mAb and EBP3 hFab have Scg3-binding affinities of 35, 8.7, 0.859 and 0.116 nM, respectively. Both anti-Scg3 EBP2 and EBP3 hFabs significantly inhibited Scg3-induced proliferation and migration of human umbilical vein endothelial cells in vitro, and alleviated DR vascular leakage and choroidal neovascularization with high efficacy. Paired assays in DR mice revealed that intravitreally injected EBP3 hFab is 26.4% and 10.3% more effective than EBP2 hFab and aflibercept, respectively, for ameliorating DR leakage. In conclusion, this study confirms the markedly improved binding affinities of hFabs compared to mAbs and further identifies EBP3 hFab as the preferred antibody to develop for anti-Scg3 therapy.

Albuminuria has been considered the golden standard biomarker for diabetic kidney disease (DKD), but appears once significant kidney damage has already occurred. Angiopoietin-2 (Angpt-2) has been implicated in the development and progression of DKD in adults. We aimed to explore the association of serum Angpt-2 levels with DKD in children and adolescents with type 1 diabetes mellitus (T1DM) of short duration (3-5 years) and to evaluate the predictive power of serum Angpt-2 in the early detection of DKD prior to the microalbuminuric phase. The current cross-sectional study included 90 children divided into three age and sex-matched groups based on urinary albumin-to-creatinine ratio (UACR): microalbuminuric diabetic group (n = 30), non-albuminuric diabetic group (n = 30), and control group (n = 30). All participants were subjected to anthropometric measurements, serum Angpt-2 and fasting lipid profile (total cholesterol, triglycerides, LDL-C, HDL-C, and Non-HDL-C) assessment. Glomerular filtration rate was estimated based on serum creatinine (eGFR-Cr). Higher serum Angpt-2 levels were detected in both diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric diabetic group. There was no detected significant difference in eGFR-Cr values across the study groups. Serum Angpt-2 was positively correlated with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR, while UACR, HbA1c, and Non-HDL-C were independent predictors for serum Angpt-2. Serum Angpt-2 at level of 137.4 ng/L could discriminate between microalbuminuric and non-albuminuric diabetic groups with AUC = 0.960 and at level of 115.95 ng/L could discriminate between the non-albuminuric diabetic group and controls with AUC = 0.976.Conclusion: Serum Angpt-2 is a promising potent biomarker for the detection of early stage of DKD in childhood T1DM before albuminuria emerges. What is Known? • Urine albumin-to-creatinine ratio (UACR) and glomerular filtration rate (GFR) are the golden standard but late biomarkers for DKD. • Angiopoietin-2 has been implicated in the development and progression of DKD in adults with diabetes, but has not been explored in T1DM children with DKD. What is New? • Higher serum angiopoietin-2 was detected in diabetic groups compared to controls and in microalbuminuric compared to non-albuminuric group. • Angiopoietin-2 correlated positively with triglycerides, LDL, Non-HDL-C, HbA1c, and UACR. • Serum angiopoietin-2 is a promising early diagnostic biomarker for DKD in children with T1DM.

TGF (transforming growth factor)-β pathway is central to blood-brain barrier development as it regulates cross talk between pericytes and endothelial cells. Murine embryos lacking TGFβ receptor Alk5 (activin receptor-like kinase 5) in brain pericytes (mutants) display endothelial cell hyperproliferation, abnormal vessel morphology, and gross germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH), leading to perinatal lethality. Mechanisms underlying how ALK5 signaling in pericytes noncell autonomously regulates endothelial cell behavior remain elusive.

Transcriptomic analysis of human brain pericytes with ALK5 silencing identified differential gene expression. Brain vascular cells isolated from mutant embryonic mice with GMH-IVH and preterm human IVH brain samples were utilized for target validation. Finally, pharmacological and genetic inhibition was used to study the therapeutic effects on GMH-IVH pathology.

Herein, we establish that the TGFβ/ALK5 pathway robustly represses ANGPT2 (angiopoietin-2) in pericytes via epigenetic remodeling. TGFβ-driven SMAD (suppressor of mothers against decapentaplegic) 3/4 associates with TGIF1 (TGFβ-induced factor homeobox 1) and HDAC (histone deacetylase) 5 to form a corepressor complex at the Angpt2 promoter, resulting in promoter deacetylation and gene repression. Moreover, murine and human germinal matrix vessels display increased ANGPT2 expression during GMH-IVH. Isolation of vascular cells from murine germinal matrix identifies pericytes as a cellular source of excessive ANGPT2. In addition, mutant endothelial cells exhibit higher phosphorylated TIE2 (tyrosine protein kinase receptor). Pharmacological or genetic inhibition of ANGPT2 in mutants improves germinal matrix vessel morphology and attenuates GMH pathogenesis. Importantly, genetic ablation of Angpt2 in mutant pericytes prevents perinatal lethality, prolonging survival.

This study demonstrates that TGFβ-mediated ANGPT2 repression in pericytes is critical for maintaining blood-brain barrier integrity and identifies pericyte-derived ANGPT2 as an important pathological target for GMH-IVH.

Sustained angiogenesis stands as a hallmark of cancer. The intricate vascular tumor microenvironment fuels cancer progression and metastasis, fosters therapy resistance, and facilitates immune evasion. Therapeutic strategies targeting tumor vasculature have emerged as transformative for cancer treatment, encompassing anti-angiogenesis, vessel normalization, and endothelial reprogramming. Growing evidence suggests the dynamic regulation of tumor angiogenesis by infiltrating myeloid cells, such as macrophages, myeloid-derived suppressor cells (MDSCs), and neutrophils. Understanding these regulatory mechanisms is pivotal in paving the way for successful vasculature-targeted cancer treatments. Therapeutic interventions aimed to disrupt myeloid cell-mediated tumor angiogenesis may reshape tumor microenvironment and overcome tumor resistance to radio/chemotherapy and immunotherapy.

The interactions between vascular cells, especially endothelial cells, and macrophages play a pivotal role in maintaining the subtle balance of vascular biology, which is crucial for angiogenesis in both healthy and diseased states. These cells are central to ensuring a harmonious balance between tissue repair and preventing excessive angiogenic activity, which could lead to pathological conditions. Recent advances in sophisticated genetic engineering vivo models and novel sequencing approaches, such as single-cell RNA-sequencing, in immunobiology have significantly enhanced our understanding of the gene expression and behavior of macrophages. These insights offer new perspectives on the role macrophages play not only in development but also across various health conditions. In this review, we explore the complex interactions between multiple types of macrophages and endothelium, focusing on their impact on new blood vessel formation. By understanding these intricate interactions, we aim to provide insights into new methods for managing angiogenesis in various diseases, thereby offering hope for the development of novel therapeutic approaches.

Cervical cancer accounts for most deaths due to cancer in women, majorly in developing nations. The culprit behind this disease is the human papillomavirus (HPV) which accounts for more than 90% of cervical cancer cases. The viral strains produce proteins that favor the knocking down of the apoptosis process and continuous growth of cells in the cervix leading to tumor growth. Proangiogenic growth factors, such as fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), angiopoietins, and other endothelial growth factors (EGF), are secreted by tumor cells and the surrounding microenvironment, which further advances the development of cancer. The extracellular domain of receptor tyrosine kinases is employed by ligands (like VEGF and EGF) to engage and activate them by inducing receptor dimerization, which facilitates the cascade impact of these factors. The tyrosine kinase domains of each receptor autophosphorylate each other, activating the receptor and initiating signaling cascades that promote angiogenesis, migration, proliferation, and survival of endothelial cells. Cancer cells benefit from its modified signaling pathways, which cause oncogenic activation. Upon early cervical cancer detection, the second-line therapy strategy involves blocking the signaling pathways with VEGF and small molecule tyrosine kinase inhibitors (TKIs). This review paper highlights the genesis of cervical cancer and combating it using VEGF and tyrosine kinase inhibitors by delving into the details of the currently available inhibitors. Further, we have discussed the inhibitor molecules that are currently in various phases of clinical trials. This paper will surely enhance the understanding of cervical cancer and its treatment approaches and what further interventions can be done to alleviate the disease currently serving as a major health burden in the developing world.

To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in treatment-naïve age-related macular degeneration (AMD) after faricimab application using optical coherence tomography angiography (OCTA).

Twenty-five eyes of 25 treatment-naïve individuals who underwent intravitreal faricimab injections for neovascular AMD (nAMD) with type 1 MNV were included. Spectral-domain optical coherence tomography (SD-OCT) images and en-face swept-source OCTA images were analyzed, and the percentage of CC flow deficit (FD%), FD average area (FDa) and FD number (FDn) in five progressive 20.0-μm-wide concentric rings (R1, R2, R3, R4 and R5) surrounding the dark halo around the MNV were calculated. Image acquisition was carried out prior to the first faricimab injection (T0) and 1 month after the injection (T1).

The topographical sub-analysis revealed noteworthy changes in all rings at T1 compared to T0. There was a notable progressive reduction in FD% at T1 compared to T0 values across all rings, indicating a gradual CC reperfusion following anti-VEGF treatment. Additionally, the average size of FD decreased after the loading phase. Although not reaching statistical significance, there was a progressive reduction in the FDa across all rings.

Our study highlights a CC FD reduction following the administration of three consecutive faricimab injections. This effect was detected in all rings surrounding the dark halo. These observations suggest a partial CC reperfusion surrounding the MNV, potentially serving as an indicator for disease regression.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer death worldwide. Curative treatments are available to a minority of patients, as HCC is often diagnosed at an advanced stage. For patients with unresectable and multifocal HCC, tyrosine kinase inhibitor drugs (TKIs) are the only potential treatment option. Despite extensive research, predictors of response to these therapies remain elusive. This study aimed to analyze the biological and histopathological characteristics of HCC patients treated with TKIs, focusing on angiogenesis and lymphangiogenesis. Immunohistochemistry quantified the expression of angiopoietin-2 (Ang2), lymphatic endothelial cells (LEC) podoplanin, and C-type Lectin Domain Family 2 (CLEC-2), key factors in neoangiogenesis and lymphangiogenesis. An increased expression of endothelial Ang2 and LEC podoplanin predicted a lower risk of metastasis. Female patients had significantly longer overall survival and survival on TKIs, associated with higher tumor expression of endothelial Ang2 and LEC podoplanin. Moreover, LEC podoplanin expression and a longer time on TKIs were independently correlated with improved survival on TKI therapy at Cox regression analysis. These findings suggest that endothelial Ang2 and LEC podoplanin could be potential biomarkers for predicting treatment outcomes and guiding therapeutic strategies in HCC patients treated with TKIs.

The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.

Redox regulation is a fundamental physiological phenomenon related to oxygen-dependent metabolism, and skeletal muscle is mainly regarded as a primary site for oxidative phosphorylation. Several studies have revealed the importance of reactive oxygen and nitrogen species (RONS) in the signaling process relating to muscle adaptation during exercise. To date, improving knowledge of redox signaling in modulating exercise adaptation has been the subject of comprehensive work and scientific inquiry. The primary aim of this review is to elucidate the molecular and biochemical pathways aligned to RONS as activators of skeletal muscle adaptation and to further identify the interconnecting mechanisms controlling redox balance. We also discuss the RONS-mediated pathways during the muscle adaptive process, including mitochondrial biogenesis, muscle remodeling, vascular angiogenesis, neuron regeneration, and the role of exogenous antioxidants.

This review investigates the therapeutic benefits of interferons (IFNs) in vitreoretinal diseases, focusing on their regulatory roles in innate immunological reactions and angiogenesis. The study aims to categorize the clinical outcomes of IFN applications and proposes a molecular mechanism underlying their action.

A systematic review was conducted using MEDLINE/PubMed, Web of Science, EMBASE, and Google Scholar databases to identify randomized clinical trials, case series, and case-control studies related to IFNs' impact on vitreoretinal diseases (1990-2022). The data synthesis involved an in-depth analysis of the anti-inflammatory and anti-angiogenesis effects of IFNs across various studies.

Our findings indicate that IFNs exhibit efficacy in treating inflammation-associated vitreoretinal disorders. However, a lack of sufficient evidence exists regarding the suitability of IFNs in angiogenesis-associated vitreoretinal diseases like choroidal neovascularization and diabetic retinopathies. The synthesis of data suggests that IFNs may not be optimal for managing advanced stages of angiogenesis-associated disorders.

While IFNs emerge as promising therapeutic candidates for inflammation-related vitreoretinal diseases, caution is warranted in their application for angiogenesis-associated disorders, especially in advanced stages. Further research is needed to elucidate the nuanced molecular pathways of IFN action, guiding their targeted use in specific vitreoretinal conditions.

Complications from diabetic retinopathy such as diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) constitute leading causes of preventable vision loss in working-age patients. Since vascular endothelial growth factor (VEGF) plays a major role in the pathogenesis of these complications, VEGF inhibitors have been the cornerstone of their treatment. Anti-VEGF monotherapy is an effective but burdensome treatment for DME. However, due to the intensive and burdensome treatment, most patients in routine clinical practice are undertreated, and therefore, their outcomes are compromised. Even in adequately treated patients, persistent DME is reported anywhere from 30% to 60% depending on the drug used. PDR is currently treated by anti-VEGF, panretinal photocoagulation (PRP) or a combination of both. Similarly, a number of eyes, despite these treatments, continue to progress to tractional retinal detachment and vitreous hemorrhage. Clearly there are other molecular pathways other than VEGF involved in the pathogenesis of DME and PDR. One of these pathways is the angiopoietin-Tie signaling pathway. Angiopoietin 1 (Ang1) plays a major role in maintaining vascular quiescence and stability. It acts as a molecular brake against vascular destabilization and inflammation that is usually promoted by angiopoietin 2 (Ang2). Several pathological conditions including chronic hyperglycemia lead to Ang2 upregulation. Recent regulatory approval of the bi-specific antibody, faricimab, may improve long term outcomes in DME. It targets both the Ang/Tie and VEGF pathways. The YOSEMITE and RHINE were multicenter, double-masked, randomized non-inferiority phase 3 clinical trials that compared faricimab to aflibercept in eyes with center-involved DME. At 12 months of follow-up, faricimab demonstrated non-inferior vision gains, improved anatomic outcomes and a potential for extended dosing when compared to aflibercept. The 2-year results of the YOSEMITE and RHINE trials demonstrated that the anatomic and functional results obtained at the 1 year follow-up were maintained. Short term outcomes of previously treated and treatment-naive eyes with DME that were treated with faricimab during routine clinical practice suggest a beneficial effect of faricimab over other agents. Targeting of Ang2 has been reported by several other means including VE-PTP inhibitors, integrin binding peptide and surrobodies.

To assess changes in choriocapillaris (CC) vascular density surrounding macular neovascularization (MNV) in age-related macular degeneration (AMD) when transitioning from various anti-VEGF treatments to faricimab, using optical coherence tomography angiography (OCTA). 25 eyes of 22 individuals who underwent intravitreal faricimab injections for neovascular AMD with type 1 MNV were included. OCTA images were obtained prior to (T0), after one (T1), and after three faricimab injections (T2); Noteworthy changes occurred in the first ring at T2 in comparison to T0. The percentage of CC flow deficit (FD%), FD average area (FDa), and FD number (FDn) in 5 rings (R1-R5) surrounding the dark halo around the MNV were calculated. A reduction in FD% at T2 compared to T0 (50.5 ± 10.2% at T0, 46.4 ± 10.6% at T2; p = 0.020) was seen, indicating CC reperfusion. Additionally, we observed a reduction in the average FDa (140.2 ± 172.1% at T0, 93.7 ± 101.8% at T2; p = 0.029). Our study highlights an FD% after three consecutive faricimab injections. The most pronounced effect was observed in the first ring, directly adjacent to the dark halo, suggesting a partial CC reperfusion surrounding the MNV, potentially indicating disease regression.

Tumor angiogenesis, the formation of new blood vessels within the tumor microenvironment, is considered a hallmark of cancer progression and represents a crucial target for therapeutic intervention. The tumor microenvironment is characterized by a complex interplay between proangiogenic and antiangiogenic factors, regulating the vascularization necessary for tumor growth and metastasis. The study of angiogenesis involves a spectrum of techniques, spanning from biomarker assessment to advanced imaging modalities. This comprehensive review aims to provide insights into the molecular intricacies, regulatory dynamics, and clinical implications of tumor angiogenesis. By delving into these aspects, we gain a deeper understanding of the processes driving vascularization in tumors, paving the way for the development of novel and effective antiangiogenic therapies in the fight against cancer.

Synthetic cannabinoids (SCs), a class of psychoactive compounds emulating the effects of natural cannabis, have prompted addiction and psychosis concerns. However, recent research has suggested potential pharmacological applications, particularly in brain angiogenesis-an essential physiological process for growth, repair, and tissue maintenance, in which new blood vasculature is formed from existing vasculature. This study explored the in vitro ability of the SC 5-fluoro ABICA to enhance new blood formation processes in human brain microvascular endothelial cells (HBMECs).

HBMECs were treated with various concentrations of 5-fluoro ABICA (1 μM, 0.1 μM, 0.01 μM, 0.001 μM, and 0.0001 μM). A comprehensive analysis was conducted, including MTT assays indicating cell viability, wound healing assays indicating migration ability, and tube formation assays indicating the angiogenesis potential of endothelial cells. Additionally, mRNA expression and protein levels of specific pro-angiogenic factors were measured, and the phosphorylation levels of glycogen synthase kinase-3β were detected in treated HBMECs through ELISA, real-time PCR, and western blotting.

Treatment with 5-fluoro ABICA effectively stimulated proliferation, migration, and tube formation in HBMECs in a dose-dependent manner; markedly increased the expression of pro-angiogenic factors; and upregulated levels of phosphorylated-GSK-3β.

Our findings demonstrate that 5-fluoro ABICA stimulates angiogenesis in endothelial cells, thus potentially offering therapeutic options for diseases associated with angiogenesis. However, further research is needed to fully understand the molecular mechanism of 5-fluoro ABICA in angiogenesis, including ethical considerations regarding its use in medical research.

Adjuvant, pre-operative intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections have been used to reduce peri-operative bleeding in eyes undergoing pars-plana vitrectomy for complications of proliferative diabetic retinopathy (PDR). To address the concern over their potential off-target effects of progressive fibrous contraction, we sought to dissect the transcriptional changes in the surgically extracted fibrovascular membranes (FVMs).

We analyzed surgically extracted FVMs from 10 eyes: 4 eyes pretreated with intravitreal bevacizumab (IVB) and 6 untreated eyes. FVMs were digested into single cells, mRNA was extracted from endothelial cell-enriched (microbead selection with CD31) and non-endothelial cell compartments, followed by RT-qPCR quantification. We then compared the relative expression of genes involved in angiogenesis, endothelial cell integrity, and myofibroblastic processes between treated and untreated FVMs.

Endothelial cells from IVB pretreated FVMs showed significant reduction of VEGFA, VEGF receptors (FLT1 and KDR), and angiopoietin 2 expression as well as increased vascular endothelial cadherin and endothelin, suggesting reduced angiogenesis and enhanced vascular integrity. The non-endothelial cell fraction showed decreased expression of VEGFA and fibronectin, without significant difference in the expression of other profibrotic factors.

Our findings confirm that adjuvant pre-operative IVB decreased fibronectin and increase endothelin-1 expression without affecting other profibrotic gene expression, uncovering an important interaction between IVB and endothelin-1 that deserves further study.

Continuous positive airway pressure (CPAP) has failed to reduce cardiovascular risk in obstructive sleep apnoea (OSA) in randomized trials. CPAP increases angiopoietin-2, a lung distension-responsive endothelial proinflammatory marker associated with increased cardiovascular risk. We investigated whether CPAP has unanticipated proinflammatory effects in patients with OSA and cardiovascular disease.

Patients with OSA (apnoea-hypopnea index [AHI] ≥15 events/h without excessive sleepiness) in the Randomized Intervention with CPAP in Coronary Artery Disease and OSA study were randomized to CPAP or usual care following coronary revascularization. Changes in plasma levels of biomarkers of endothelial (angiopoietin-2, Tie-2, E-selectin, vascular endothelial growth factor [VEGF-A]) and lung epithelial (soluble receptor of advanced glycation end-products [sRAGE]) function from baseline to 12-month follow-up were compared across groups and associations with cardiovascular morbidity and mortality assessed.

Patients with OSA (n = 189; 84% men; age 66 ± 8 years, BMI 28 ± 3.5 kg/m2, AHI 41 ± 23 events/h) and 91 patients without OSA participated. Angiopoietin-2 remained elevated whereas VEGF-A declined significantly over 12 months in the CPAP group (n = 91). In contrast, angiopoietin-2 significantly declined whereas VEGF-A remained elevated in the usual care (n = 98) and OSA-free groups. The changes in angiopoietin-2 and VEGF-A were significantly different between CPAP and usual care, whereas Tie-2, sRAGE and E-selectin were similar. Greater 12-month levels of angiopoietin-2 were associated with greater mortality. Greater CPAP levels were associated with worse cardiovascular outcomes.

Greater CPAP levels increase proinflammatory, lung distension-responsive angiopoietin-2 and reduce cardioprotective angiogenic factor VEGF-A compared to usual care, which may counteract the expected cardiovascular benefits of treating OSA.

National Institutes of Health/National Heart, Lung, and Blood Institute; Swedish Research Council; Swedish Heart-Lung Foundation; ResMed Foundation.

The development and differentiation of endothelial cells (ECs) are fundamental processes with significant implications for both health and disease. ECs, which are found in all organs and blood vessels, play a crucial role in facilitating nutrient and waste exchange and maintaining proper vessel function. Understanding the intricate signaling pathways involved in EC development holds great promise for enhancing vascularization, tissue engineering, and vascular regeneration. Hematopoietic stem cells originating from hemogenic ECs, give rise to diverse immune cell populations, and the interaction between ECs and immune cells is vital for maintaining vascular integrity and regulating immune responses. Dysregulation of vascular development pathways can lead to various diseases, including cancer, where tumor-specific ECs promote tumor growth through angiogenesis. Recent advancements in single-cell genomics and in vivo genetic labeling have shed light on EC development, plasticity, and heterogeneity, uncovering tissue-specific gene expression and crucial signaling pathways. This review explores the potential of ECs in various applications, presenting novel opportunities for advancing vascular medicine and treatment strategies.

NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood.

We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis.

NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; βTOPCAT=0.539; P<0.0001; βPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; βTOPCAT=0.571; P<0.0001; βPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations.

Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Age-related macular degeneration (AMD) can lead to irreversible impairment of visual function, and the number of patients with AMD has been increasing globally. The immunoinflammatory theory is an important pathogenic mechanism of AMD, with macrophages serving as the primary inflammatory infiltrating cells in AMD lesions. Its powerful immunoinflammatory regulatory function has attracted considerable attention. Herein, we provide an overview of the involvement of macrophage-regulated immunoinflammation in different stages of AMD. Additionally, we summarize novel therapeutic approaches for AMD, focusing on targeting macrophages, such as macrophage/microglia modulators, reduction of macrophage aggregation in the subretinal space, modulation of macrophage effector function, macrophage phenotypic alterations, and novel biomimetic nanocomposites development based on macrophage-associated functional properties. We aimed to provide a basis and reference for the further exploration of AMD pathogenesis, developmental influences, and new therapeutic approaches.

Cold-inducible RNA binding Protein (CIRBP) has been shown to be a potent inflammatory mediator and could serve as a novel biomarker for inflammation. Systemic inflammatory response syndrome (SIRS) and capillary leak syndrome (CLS) are frequent complications after pediatric cardiac surgery increasing morbidity, therefore early diagnosis and therapy is crucial. As CIRBP serum levels have not been analyzed in a pediatric population, we conducted a clinical feasibility establishing a customized magnetic bead panel analyzing CIRBP in pediatric patients undergoing cardiac surgery.

A prospective hypothesis generating observational clinical study was conducted at the German Heart Center Berlin during a period of 9 months starting in May 2020 (DRKS00020885, https://drks.de/search/de/trial/DRKS00020885). Serum samples were obtained before the cardiac operation, upon arrival at the pediatric intensive care unit, 6 and 24 h after the operation in patients up to 18 years of age with congenital heart disease (CHD). Customized multiplex magnetic bead-based immunoassay panels were developed to analyze CIRBP, Interleukin-1β (IL-1β), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-10 (IL-10), Monocyte chemotactic protein 1 (MCP-1), Syndecan-1 (SDC-1), Thrombomodulin (TM), Vascular endothelial growth factor (VEGF-A), Angiopoietin-2 (Ang-2), and Fibroblast growth factor 23 (FGF-23) in 25 µl serum using the Luminex MagPix® system.

19 patients representing a broad range of CHD (10 male patients, median age 2 years, 9 female patients, median age 3 years) were included in the feasibility study. CIRBP was detectable in the whole patient cohort. Relative to individual baseline values, CIRBP concentrations increased 6 h after operation and returned to baseline levels over time. IL-6, IL-8, IL-10, and MCP-1 concentrations were significantly increased after operation and except for MCP-1 concentrations stayed upregulated over time. SDC-1, TM, Ang-2, as well as FGF-23 concentrations were also significantly increased, whereas VEGF-A concentration was significantly decreased after surgery.

Using customized magnetic bead panels, we were able to detect CIRBP in a minimal serum volume (25 µl) in all enrolled patients. To our knowledge this is the first clinical study to assess CIRBP serum concentrations in a pediatric population.

Breakdown of the neurovascular unit is associated with blood-brain barrier (BBB) leakiness contributing to cognitive decline and disease pathology in the early stages of Alzheimer's disease (AD). Vascular stability depends on angiopoietin-1 (ANGPT-1) signalling, antagonised by angiopoietin-2 (ANGPT-2) expressed upon endothelial injury. We examined the relationship between CSF ANGPT-2 and CSF markers of BBB leakiness and core AD biomarkers across three independent cohorts: (i) 31 AD patients and 33 healthy controls grouped according to their biomarker profile (i.e., AD cases t-tau > 400 pg/mL, p-tau > 60 pg/mL and Aβ42 < 550 pg/mL); (ii) 121 participants in the Wisconsin Registry for Alzheimer's Prevention or Wisconsin Alzheimer's Disease Research study (84 participants cognitively unimpaired (CU) enriched for a parental history of AD, 20 participants with mild cognitive impairment (MCI), and 17 with AD); (iii) a neurologically normal cohort aged 23-78 years with paired CSF and serum samples. CSF ANGPT-2, sPDGFRβ, albumin and fibrinogen levels were measured by sandwich ELISA. In cohort (i), CSF ANGPT-2 was elevated in AD and correlated with CSF t-tau and p-tau181 but not Aβ42. ANGPT-2 also correlated positively with CSF sPDGFRβ and fibrinogen - markers of pericyte injury and BBB leakiness. In cohort (ii), CSF ANGPT-2 was highest in MCI and correlated with CSF albumin in the CU and MCI cohorts but not in AD. CSF ANGPT-2 also correlated with CSF t-tau and p-tau and with markers of neuronal injury (neurogranin and α-synuclein) and neuroinflammation (GFAP and YKL-40). In cohort (iii), CSF ANGPT-2 correlated strongly with the CSF/serum albumin ratio. Serum ANGPT-2 showed non-significant positive associations with CSF ANGPT-2 and the CSF/serum albumin ratio. Together, these data indicate that CSF and possibly serum ANGPT-2 is associated with BBB leakiness in early AD and is closely related to tau pathology and neuronal injury. The utility of serum ANGPT-2 as a biomarker of BBB damage in AD requires further study.

It has been demonstrated that cold atmospheric plasma (CAP) accelerates the wound healing process, however the underlying molecular pathways behind this effect remain unclear. Thus, the goal of the proposed investigation is to elucidate the therapeutic advantages of CAP on angiogenesis, pyroptotic, oxidative stress, and inflammatory mediators during the wound-healing mechanisms associated with diabetes. Intraperitoneal administration of streptozotocin (STZ, 60 mg/Kg) of body weight was used to induce type-1 diabetes. Seventy-five male mice were randomized into 3 groups: the control non-diabetic group, the diabetic group that was not treated, and the diabetic group that was treated with CAP. The key mediators of pyroptosis and its impact on the slow healing process of diabetic wounds were examined using histological investigations employing H&E staining, immunohistochemistry, ELISA, and Western blotting analysis. Angiogenesis proteins (VEGF, Ang-1, and HO-1) showed a significant decline in expression concentrations in the diabetic wounds, indicating that diabetic animals' wounds were less likely to heal. Furthermore, compared to the controls, the major mediators of pyroptosis (NLRP-3, IL-1β, and caspase-1), oxidative stress (iNOS and NO), and inflammation (TNF-α and IL-6) have higher expression levels in the diabetic wounds. These factors substantially impede the healing mechanism of diabetic wounds. Interestingly, our results disclosed the therapeutic impacts of CAP treatment in the healing process of diabetic wounds via significantly regulating the expression levels of angiogenesis, pyroptosis, oxidative stress and pro-inflammatory mediators. Our findings demonstrated the curative likelihood of CAP and the underlying mechanisms for enhancing the healing process of diabetic wounds.

Tumor hypoxia resulting from abnormal and dysfunctional tumor vascular network poses a substantial obstacle to immunotherapy. In fact, hypoxia creates an immunosuppressive tumor microenvironment (TME) through promoting angiogenesis, metabolic reprogramming, extracellular matrix remodeling, epithelial-mesenchymal transition (EMT), p53 inactivation, and immune evasion. Vascular normalization, a strategy aimed at restoring the structure and function of tumor blood vessels, has been shown to improve oxygen delivery and reverse hypoxia-induced signaling pathways, thus alleviates hypoxia and potentiates cancer immunotherapy. In this review, we discuss the mechanisms of tumor tissue hypoxia and its impacts on immune cells and cancer immunotherapy, as well as the approaches to induce tumor vascular normalization. We also summarize the evidence supporting the use of vascular normalization in combination with cancer immunotherapy, and highlight the challenges and future directions of this overlooked important field. By targeting the fundamental problem of tumor hypoxia, vascular normalization proposes a promising strategy to enhance the efficacy of cancer immunotherapy and improve clinical outcomes for cancer patients.

Impaired angiogenesis, measured as serum levels of angiogenic growth factors, may be among the mechanisms underlining aortic stiffness in diabetes patients. We studied the association between aortic stiffness and circulating angiogenic growth factors in type 2 diabetes (T2DM) patients without any organ damage.

In a case-control design, aortic pulse wave velocity (PWV), augmentation index (AIx), and aortic blood pressures (BPs) were measured in 140 T2DM patients and 110 nondiabetic controls. Fasting blood samples were collected to measure the levels of angiopoietin- (Ang-) 1, Ang-2, and vascular endothelial growth factor-A (VEGF).

Compared to nondiabetes participants, T2DM patients had increased PWV (8.7 ± 1.5 vs. 7.6 ± 1.3, p = 0.031), aortic pulse BP (58 ± 20 vs. 49 ± 17, p = 0.011), Ang-2 (838 (473-1241) vs. 597 (274-1005), p = 0.018), and VEGF (72.2 (28-201.8) vs. 48.4 (17.4-110.1), p = 0.025) but reduced levels of AIx (21.7 ± 13.8 vs. 34 ± 12.9, p < 0.001) and Ang-1 (33.1 (24.7-42.1) vs. 41.1 (30-57.3), p = 0.01). In all study participants, compared to those in the lower tertile, participants in the upper tertile of Ang-2 had increased odds of PWV (2.01 (1.17-3.84), p = 0.004), aortic systolic BP (1.24 (1.04-1.97), p = 0.011), and aortic pulse BP (1.19 (1.04-1.82), p = 0.041) but reduced odds of AIx (0.84 (0.71-0.96), p = 0.014) in multivariable-adjusted models.

In our study population, increased circulating Ang-2 was associated with increased levels of aortic stiffness parameters.