Repairing the impaired gut vascular barrier as a novel therapeutic target for prolonged postoperative ileus: A scoping review

Abstract

Prolonged postoperative ileus (PPOI) is a common post-surgery iatrogenic complication, with an incidence rate of 10%-28%. Severe PPOI delays postoperative recovery, prolongs hospital stay, and further increases healthcare costs. The pathogenesis of PPOI is extremely complex. The persistent and excessive immune-inflammatory response is currently considered to be the main pathological mechanism of PPOI. Gut vascular barrier (GVB) damage and the resulting vascular inflammatory response are two key factors responsible for sustaining persistent intestinal inflammation in PPOI. This article comprehensively reviews the effects of intestinal microvascular endothelial cell (IMVEC) dysfunction, increased GVB permeability, pathological angiogenesis, and intestinal microvascular hemodynamic alterations on PPOI. Our review indicates that these GVB-related mechanisms collectively exacerbate intestinal inflammation and dysmotility, contributing to the persistence of PPOI. It also discusses the potential of improving IMVEC function, reducing GVB permeability, inhibiting pathological angiogenesis, and ameliorating intestinal microcirculation for preventing and treating PPOI. In conclusion, targeting GVB dysfunction and associated vascular pathology represents a promising therapeutic strategy. Thus, we propose that restoring the impaired GVB may serve as a potential target for therapeutic intervention in PPOI.

Key Words: Gut vascular barrier; Prolonged postoperative ileus; Intestinal microvascular endothelial cells; Therapeutic target; Vascular immunity

Core Tip: Prolonged postoperative ileus (PPOI) is a common iatrogenic complication following surgery, with an incidence rate ranging from 10% to 28%. Damage to the gut vascular barrier (GVB) and the subsequent vascular inflammatory response are key factors that contribute to the persistence of intestinal inflammation in PPOI. This review comprehensively examines the impact of intestinal microvascular endothelial cell dysfunction, increased GVB permeability, pathological angiogenesis, and alterations in intestinal microvascular hemodynamics on PPOI. It suggests that restoring the impaired GVB may present a promising therapeutic target for managing PPOI.

INTRODUCTION

Prolonged postoperative ileus (PPOI) is a temporary gastrointestinal motility disorder caused by non-mechanical factors after surgery. The incidence rate of PPOI is as high as 10%-28%[1]. PPOI not only prolongs the postoperative hospital stay but also increases the postoperative mortality rate and total medical costs[2]. In 2011, the total annual expenditure on PPOI in the United States was up to 12.3 billion USD[3]. Despite this, the pathophysiological mechanisms of PPOI have not yet been fully elucidated. Current studies suggest that the immune-inflammatory response following intestinal barrier damage is a key factor in the pathogenesis of PPOI[4,5]. Therefore, improving intestinal barrier permeability has been proposed as a novel therapeutic target for intervention in PPOI[5].

The gut vascular barrier (GVB) was first reported by Spadoni et al[6] in the intestinal subepithelial layer of mice infected with Salmonella typhimurium in 2015. It has been identified as a novel barrier, distinct from the conventional microbial, chemical, physical, and immune barriers[6,7]. The GVB exhibits selective permeability: Under normal physiological conditions, it permits the passage of small molecules and nutrients but prevents the translocation of macromolecules, cells, and bacteria into the circulation[7]. However, pathological insults, such as infection by invasive pathogens, can breach the GVB, allowing bacterial dissemination and triggering systemic inflammatory cascades[7]. Indeed, structural and functional impairment of the GVB constitutes a key pathological basis for intestinal inflammation, as demonstrated by multiple studies reporting loss of tight junction (TJ) integrity, increased expression of plasmalemma vesicle-associated protein-1 (PV-1), and inflammation-induced microvascular leakage[8-11]. Conversely, interventions that restore GVB integrity, such as kaempferol and berberine, have been shown to attenuate intestinal inflammation and improve motility by preserving endothelial junctional proteins and reducing permeability[12,13]. Transendothelial migration of leukocytes and the subsequent immunoinflammatory response underlie the key pathological mechanism of PPOI. This article provides a detailed review of the anatomical structure and physiological functions of the GVB, along with its pathological alterations during PPOI. We aim to highlight, for both clinicians and researchers, the critical importance of repairing the impaired GVB in preventing and ameliorating PPOI, thereby offering a novel perspective for its clinical management.

PATHOPHYSIOLOGICAL MECHANISMS OF PPOI

Anesthesia, pneumoperitoneum, surgical manipulation, massive hemorrhage, large-volume fluid administration, and use of opioid analgesics are the main inducing factors of PPOI (Figure 1). The fundamental pathological mechanism of PPOI involves abnormal neuronal signaling caused by inflammatory cell infiltration into the muscular layer following intestinal barrier injury[14]. Prolonged intravenous anesthesia and excessive use of opioids lead to the systemic nonselective activation of mu-opioid receptors in the central nervous system, which results in the inhibition of intestinal peristalsis[15,16]. Carbon dioxide (CO₂) is the most commonly employed gas for establishing pneumoperitoneum. Research indicates that CO₂ suppresses the infiltration of anti-inflammatory macrophages into the intestinal muscular layer by modulating their intracellular pH via carbonic anhydrases[17]. Additionally, CO₂ potentiates intestinal inflammation by promoting the release of immunoglobulin A from immunoinflammatory cells[18]. Perioperative fluid overload activates the renin-angiotensin-aldosterone system, resulting in intestinal tissue edema. This edema elevates intra-abdominal pressure, reduces mesenteric blood flow, and induces tissue ischemia and hypoxia, thereby exacerbating intestinal inflammation[19]. Massive hemorrhage induces circulatory hypovolemia and the consequent ischemic hypoxia, thereby intensifying existing intestinal inflammation. Surgical manipulation and injury release an enormous amount of inflammatory factors, chemokines, and damage-associated molecular patterns[20,21]. These cytokines promote mast cell degranulation by inhibiting the transient receptor potential ankyrin 1-mediated cyclic AMP response element-binding protein/WNT1-inducible signaling protein 1 signaling pathway[4]. Substances [including chymase, histamine, and interleukin (IL)] released during mast cell degranulation compromise the intestinal epithelial barrier and simultaneously activate inflammatory cells[20,22]. Dendritic cells exert their antigen-presenting function following activation by CCR7[21]. Orchestrated by the gut microbiota, they activate muscularis resident macrophages and neutrophils[23]. Dendritic cells additionally induce the migration of T helper type 1 memory cells to intestinal regions remote from the surgical site, where they trigger gut hypomotility[24]. The binding of damage-associated molecular patterns to the purinergic 2X7 receptor activates macrophages[25]. The activated macrophages trigger inflammatory cascades through various signaling pathways, including toll like receptors (TLR), nuclear factor kappa-B (NF-κB)/mitogen-activated protein kinases (MAPK), phosphatidylinositol 3 kinase/protein kinase B (Akt)/NF-κB, and Janus kinase 2/signal transducer and activator of transcription 3[26-29]. IL-17A released by macrophages induces monocytes and neutrophils to express nitric oxide (NO), resulting in the relaxation of the intestinal circular muscle[30]. C-X-C motif chemokine ligand 1 secreted by macrophages can directly inhibit the intestinal contractile activity[31]. Activated neutrophils infiltrate the muscular layer and exacerbate intestinal inflammation by releasing reactive oxygen species (ROS) and neutrophil extracellular traps[32,33]. Granzyme B, interferon-γ, and tumor necrosis factor-α (TNF-α) produced by T lymphocytes activate the inflammatory phenotype in enteric glial cells[34,35]. These inflammatory signals are transmitted via visceral afferent nerves to the spinal cord, activating the sympathetic nervous system, and are subsequently relayed through efferent nerves to the intestinal muscular layer[36]. Additionally, severe inflammatory stimuli can ascend via spinal nerves to the brainstem, activating the hypothalamic and pontine nuclei, which suppress vagal nerve activity and further delay intestinal peristalsis[36].

Figure 1 Pathological factors of prolonged postoperative ileus and the inflammatory response mediated by intestinal microvascular endothelial cells. A: Laparoscopic photo of the small intestine before surgical manipulation in the patient with colon cancer; B: Laparoscopic photo of the small intestine after surgical manipulation in the patient with colon cancer; C: Inflammatory response mediated by inflammatory response mediated by intestinal microvascular endothelial cells in prolonged postoperative ileus. Created in BioRender (Supplementary material).

Recent studies have established that intestinal microvascular endothelial cells (IMVECs), a critical component of the intestinal barrier, actively participate in the occurrence and development of PPOI by mediating vascular inflammatory responses (Figure 1). Ischemia-reperfusion injury signaling activates the focal adhesion kinase pathway, promoting the generation of oxygen-free radicals in endothelial cells and reducing the expression of vascular endothelial-cadherin (VE-cadherin) and β-catenin between endothelial cells[37]. Damaged endothelial cells highly express intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-β, insulin-like growth factor-1, and insulin-like growth factor-1 receptor and promote the infiltration of inflammatory cells into the muscular layer[38]. Under hemodynamic disturbances, mechanical signals are transduced to endothelial cells through a mechanosensory complex composed of platelet endothelial cell adhesion molecule-1, VE-cadherin, and vascular endothelial growth factor (VEGF) reporter 2[39]. Activated endothelial cells initiate the phosphorylation of Akt and endothelial NO synthase (eNOS), generating NO[40]. High concentrations of NO react with the superoxide anion to form peroxynitrite anions, nitroxyl anions, and nitrogen dioxide, inducing oxidative stress and triggering cytotoxic processes[41,42]. Activated endothelial cells release various pro-inflammatory factors (e.g., IL-4 and IL-13), adhesion molecules [e.g., ICAM-1, vascular cell adhesion molecule-1 (VCAM-1), and von Willebrand factor (vWF)], and vasoactive factors (e.g., VEGF, transforming growth factor-β, and ROS), all of which are involved in inflammation, angiogenesis, and oxidative stress[43]. Severe intestinal inflammation and oxidative stress decrease the number of interstitial cells of Cajal and cause vacuolization and degenerative changes in myenteric neuronal cells, ultimately resulting in impaired intestinal motility[44-46].

GVB IS AN INDEPENDENT INTESTINAL BARRIER STRUCTURE

Anatomy of GVB

The GVB is present underneath the intestinal epithelium. It is primarily composed of a monolayer of IMVEC and is supported by enteric glial cells and pericytes[6] (Figure 2). IMVECs are connected through TJ and adherens junction (AJ). The TJ is composed of occludin, zonula occludens-1 (ZO-1), cingulin, and junctional adhesion molecule-A. The AJ comprises VE-cadherin and β-catenin[6]. CD31 and vWF are characteristic phenotypic markers of IMVECs. PV-1 is a distinctive protein of IMVECs[6,47]. Mature IMVECs have abundant vesicles, microfilament bundles, and Weibel-Palade bodies in the cytoplasm and exhibit tube-forming ability[48]. Under physiological conditions, 4-kD fluorescein isothiocyanate (FITC) dextran can freely pass through the GVB, whereas ≥ 70-kD FITC-dextran, bacteria, and cells cannot[6]. This size-selective property is critical because it prevents translocation of bacteria and large macromolecules from the gut lumen into the circulation, thereby protecting the host from systemic endotoxemia and excessive immune activation.

Figure 2 Anatomy of the gut vascular barrier. The gut vascular barrier is present underneath the intestinal epithelium. It is primarily composed of a monolayer of intestinal microvascular endothelial cells (IMVECs) and is supported by enteric glial cells and pericytes. IMVECs are connected through tight junction and adherens junction. Plasmalemma vesicle-associated protein-1 is a distinctive protein of IMVECs. Created in BioRender (Supplementary material).

Development and functional maturation of GVB

The canonical Wnt/β-catenin signaling pathway plays a crucial role in maintaining the structural and functional maturity of the endothelial barrier[49]. Following the activation of the Wnt/β-catenin signaling pathway, β-catenin activity and Axin2 expression are upregulated[50]. This effect increases the expression of TJ and AJ while simultaneously reducing that of PV-1, thereby maintaining the structural and functional integrity of the GVB[50]. The VEGF/NOTCH pathway regulates the normal structure and function of the intestinal vasculature, though additional studies are required[51]. S100B, a cytosolic calcium-binding protein secreted by enteric glial cells, regulates the expression of PV-1, β-catenin, and occludin in IMVECs through the S100B/ADAM10 and S100B/caspase-8/β-catenin signaling pathways[52,53]. Pericytes play a crucial role in maintaining the endothelial barrier function. Angiopoietin-1 secreted by pericytes can reduce the permeability of the intestinal vasculature and promote the proliferation of endothelial cells and angiogenesis[54]. The gut microbiota can facilitate the maturation and functional development of the GVB[55]. In neonates, the gut microbiota is not fully developed, and the Wnt pathway shows increased activity, leading to the incomplete establishment of the barrier function of the GVB[55]. Post-colonization, microbial signals downregulate PV-1 and enhance the production of TJ/AJ proteins, thereby accelerating GVB maturation. Additionally, bacterial ligands enhance the proliferation and tube-formation capability of IMVECs, thereby promoting angiogenesis and vessel sprouting[55,56]. The maturation of GVB relies on the integration of multiple signaling pathways (such as Wnt/β-catenin, VEGF/Notch, and gut microbiota signals). These mechanisms are inhibited or disrupted to varying degrees following surgery, which may result in PPOI.

Physiological functions of GVB

Barrier function of GVB: The GVB constitutes the final barrier preventing translocation of bacteria, macromolecules, cells, and other luminal constituents into the bloodstream[57]. The endothelial glycocalyx, intercellular junctions, and cellular components collectively constitute the barrier function of the GVB[58] (Figure 3A). The endothelial glycocalyx coating the surface of IMVECs prevents these cells from direct exposure to blood flow, blocking fluid shear stress-mediated activation of the NF-κB signaling pathway and phosphorylation of Akt, which maintains the physical barrier function of the GVB[59,60]. The intercellular junctional complexes form a “fence” between adjacent IMVECs, preventing bacteria and cells from entering the circulatory system[61]. PV-1 and VE-cadherin constitute the essential components of fenestrae and caveolae in IMVECs. In gut-derived sepsis, IMVECs exhibit upregulated PV-1 expression and reduce the level of VE-cadherin, compromising the GVB[62]. The increased permeability of the GVB allows macromolecules and bacteria from the gut to enter the systemic circulation and invade distant organs[62].

Figure 3 The physiological functions of the gut vascular barrier. A: Physiological barrier function of the gut vascular barrier (GVB); B: Anti-adhesion function of the GVB; C: Absorptive function of the GVB; D: Immunological function of the GVB. IL: Interleukin; NO: Nitric oxide; VLDL: Very low-density lipoprotein; TLR: Toll like receptors; NF-κB: Nuclear factor kappa-B; MAPK: Mitogen-activated protein kinases. Created in BioRender (Supplementary material).

Beyond its physical barrier role, the GVB also functions as an anti-adhesive interface (Figure 3B). Under normal pH, the endothelial glycocalyx is a negatively charged gel layer that repels the adhesion of similarly negatively charged leukocytes, platelets, bacteria, and viruses[63]. When the negatively charged gel layer is disrupted, endothelial cells release abundant adhesion molecules (such as L-selectin and P-selectin) under inflammatory stimulation[64]. This phenomenon enhances leukocyte adhesion to the endothelium and exacerbates local inflammation[64]. NO generated by eNOS and inducible NO synthase (iNOS) resists the adhesion of platelets, erythrocytes, and leukocytes to the endothelium via s-nitrosylation[65,66]. Reduced NO bioavailability, diminished NO production, or excessive NO generation in IMVECs potentiate the adhesion of leukocytes and platelets[65,67,68]. The physical barrier impairment of GVB leads to a massive invasion of pathogens, which results in the activation of IMVEC-mediated neuroinflammatory responses that inhibit intestinal peristalsis.

Absorptive function of GVB: Nutrient absorption refers to a direct transfer of substances or particles from the intestinal lumen into the bloodstream without prior digestion[69] (Figure 3C). The permeability-surface area product of the GVB and the capillary blood flow in the intestinal villi directly influence the rate and efficiency of absorption[70]. Small-molecule lipids in the chyme are first processed into chylomicrons and very-low-density lipoproteins with a diameter of less than 75 nm in the smooth endoplasmic reticulum and Golgi apparatus of intestinal epithelial cells and are then released into the basolateral plasma membrane[71]. IMVECs transport these chylomicrons and very-low-density lipoproteins into the bloodstream via endocytosis[69,71]. Glucose is first transported into the cytoplasm of the intestinal epithelial cells via sodium-glucose cotransporter 1 and then exported from the cells through glucose transporter 2 and vesicular transport[72]. The glucose reaching the basolateral side enters the bloodstream through fenestrations on the surface of IMVECs[72]. Amino acids derived from the digestion and hydrolysis of proteins are absorbed through internalization by IMVECs[73]. Other substances, such as small molecules, ions, and gases, can enter the bloodstream through transcellular and paracellular pathways. Note that the role of the absorptive function of GVB in the development of PPOI is yet to be clarified.

Immune function of GVB: The GVB also functions as an immunoprotective barrier (Figure 3D). The proteoglycans in the glycocalyx (e.g., syndecan-1, syndecan-3, and biglycan) can scavenge chemokines, inhibit pro-inflammatory factor expression, block leukocyte migration, and induce autophagy of proinflammatory M1 macrophages[74]. High-molecular-weight hyaluronic acid exhibits anti-inflammatory and immunosuppressive properties. In addition, it inhibits M1 macrophage polarization and downregulates inflammatory factor expression by suppressing the activation of the glucoseregulated protein 78 kD/NF-κB, MAPK, and NF-κB signaling pathways and by binding to CD44 variants[75-77]. In contrast, the accumulation of low-molecular-weight hyaluronic acid promotes immune-inflammatory responses[78]. It downregulates VE-cadherin, increases endothelial permeability[79], and binds erythrocyte CD44 to induce red blood cell aggregation[80]. Endothelial-derived IL-1α initially promotes neutrophil adhesion in the early phase of PPOI and enhances the bactericidal activity of transendothelial neutrophils in the later phase by triggering oxidative phosphorylation, thereby activating innate immunity[81]. Upon recognizing major histocompatibility complex class I, enteric glial cells present antigens to CD8⁺ T cells and concurrently activate their own innate immune responses through the TLR/NF-κB/p38 MAPK signaling pathway[82,83]. Pericytes reduce the expression of adhesion molecules (platelet endothelial cell adhesion molecule-1 and ICAM-1) and pro-inflammatory cytokines (C-C motif ligand 2 and IL-6) in endothelial cells by inhibiting the activity of connexin 43[84]. The vascular inflammatory response involving GVB directly or indirectly participates in chronic intestinal inflammation and neuronal inhibitory effects during PPOI.

IMPAIRMENT OF GVB AS A CRITICAL FACTOR IN SUSTAINING INTESTINAL INFLAMMATION DURING PPOI

Disruption of the GVB and subsequent transendothelial migration of circulating leukocytes into the muscularis are central pathological events in PPOI (Figure 4). Loss of GVB integrity allows immune cells to infiltrate the intestinal wall, where they release pro-inflammatory cytokines, proteases, and reactive species. These mediators further degrade endothelial junctional proteins (e.g., VE-cadherin and ZO-1), increase vascular permeability, and upregulate adhesion and procoagulant molecules on IMVECs, such as ICAM-1, VCAM-1, and tissue factor. Together, these processes can form a feed-forward loop in which inflammation perpetuates GVB impairment, leading to tissue edema, microcirculatory dysfunction, altered neuronal signaling, and impaired gastrointestinal motility[57]. Thus, in PPOI, the GVB serves not merely as a regulatory factor for intestinal inflammation but also as a target of potential attack.

Figure 4 Impairment of the gut vascular barrier as a critical factor in sustaining intestinal inflammation during prolonged postoperative ileus. A: Intestinal microvascular endothelial cell dysfunction; B: Increased permeability of the gut vascular barrier; C: Pathological angiogenesis; D: Hemodynamic changes. NO: Nitric oxide; iNOS: Inducible nitric oxide synthase; INF-γ: Interferon-γ; VE-cadherin: Vascular endothelial-cadherin; VEGF: Vascular endothelial growth factor; vWF: Von Willebrand factor. Created in BioRender (Supplementary material).

Endothelial cell dysfunction

IMVEC dysfunction refers to a spectrum of maladaptive alterations in their functional phenotype, including reduced NO bioavailability, activation of pro-inflammatory phenotypes, and enhanced membrane permeability, among others[85]. These changes can initiate local tissue inflammation, edema, and hypoxic injury, ultimately contributing to functional disturbance. Key regulators implicated in endothelial dysfunction include the angiopoietin-Tie2 axis, adrenomedullin, and VE-cadherin[58]. Under inflammatory conditions, IMVECs exhibit reduced iNOS expression and diminished NO production, resulting in impaired endothelial anti-adhesive function[86]. Dysfunctional IMVECs secrete inflammatory factors (IL-6, IL-8, and TNF-α), chemokines [integrin α(v)β(3)], adhesion molecules (E-selectin, thromboxane B2, and ICAM-1), pro-angiogenic factors (VEGF-A), and apoptosis-related proteins (caspase-3)[8,9]. Inflammatory cytokines IL-6, IL-10, and TNF-α are considered independent risk factors for inducing PPOI[87]. After the NLRP3 inflammasome in endothelial cells is activated, the released IL-1β and caspase-1 exacerbate intestinal ischemia/reperfusion injury[88]. ICAM-1, integrin α(v)β(3), and fractalkine promote platelet activation, rolling, and adhesion to endothelial cells, thereby inducing intestinal inflammation[9]. IMVECs overexpressing VEGF-A and matrix metallopeptidase 14 promote microvascular angiogenesis in inflammatory bowel diseases[10,11]. Pathological angiogenesis is recognized as an active driver of chronic intestinal inflammation. Under TNF-α induction, the highly expressed apoptotic proteins in IMVECs—caspase-1 and caspase-3—can disrupt the intestinal mucosal barrier[89].

Increased permeability of GVB

Surgical and traumatic stress activates the hypothalamic-pituitary-adrenal axis and increases the total number of circulating glucocorticoids, which can downregulate TJ proteins in both epithelial and endothelial cells. This phenomenon leads to impaired barrier function[90-92]. Sorribas et al[93] reported that chronic intraperitoneal administration of isoproterenol in mice upregulates PV-1 expression in IMVECs, increases GVB permeability, and permits trans-barrier passage of 70-kDa FITC dextran into systemic circulation. Increased GVB permeability promotes transendothelial migration of circulating macrophages, monocytes, and lymphocytes[94]. Infiltration of the muscularis propria by myeloid leukocytes induces enteric neuron paralysis, precipitating PPOI[29]. Inflammatory triggers cause IMVECs to synthesize and secrete a large amount of VEGF-A[95] also known as vascular permeability factor. The activation of the VEGF-A/phospholipase Cβ2, hypoxia-inducible factor/VEGF-A, and VEGF/Akt/MAPK signaling pathways directly induces an increase in GVB permeability[95-97]. Increased GVB permeability is primarily manifested as the degradation of the endothelial glycocalyx, hydrolysis of junction proteins, and proliferation of fenestrae/caveolae[59,98,99]. Elevated levels of TNF-α promote the degradation of the endothelial glycocalyx[100], which further activates plasma cells and neuroinflammatory responses, thereby triggering mucosal immunity[101]. Infection of IMVECs by interferon-γ disrupts the VE-cadherin membrane localization and induces the internalization of VE-cadherin through the VEGF-A pathway, ultimately leading to increased GVB permeability and intestinal inflammation[102]. Intestinal inflammation further impairs the GVB through a positive feedback loop, leading to reduced endothelial TJ and AJ proteins, increased PV-1 expression, and elevated fenestrae density in endothelial cells[103]. To circulate repeatedly, the inflammatory storm continuously upgrades, which in turn suppresses the activity of the enteric nervous system and delays intestinal motility[29].

Pathological angiogenesis

Pathological angiogenesis is closely associated with chronic intestinal inflammation, postoperative intra-abdominal adhesions, and postoperative ileus[104,105]. In the inflamed intestinal tissue, a cascade of endothelial and platelet-derived signals drives the formation of new microvessels that are structurally and functionally abnormal. These nascent vessels frequently lack proper maturation and barrier function, which in turn amplifies tissue inflammation and compromises organ function. For example, activated STAT1 upregulates transglutaminase-2 in IMVECs; transglutaminase-2 can interact with VEGF receptor 2 and enhance its phosphorylation (reported at residues such as Tyr1059 and Tyr1214), potentiating downstream VEGF-dependent angiogenic signaling[105]. Platelets, displaced toward the vessel wall under disturbed flow conditions, adhere to activated IMVECs and release pro-angiogenic mediators, including VEGF-A, further stimulating endothelial proliferation, migration, and tubulogenesis[9]. Inflammatory mediators, tissue factors, chemokines, and other molecules can also stimulate endothelial cell proliferation, migration, and tubulogenesis via NO-VEGF and matrix metallopeptidase signaling pathways[106]. However, angiogenesis occurring in an inflammatory milieu is qualitatively different from physiological angiogenesis. Due to differential regulation by inflammatory factors (e.g., IL-1β, IL-6, IL-8, IL-17, IL-30, and TNF-α), reactive oxygen/nitrogen species (e.g., ROS and NO), adhesion molecules (e.g., nectin cell adhesion molecule 4, basal cell adhesion molecule, VCAM-1, and ICAM-1), and integrins result in the formation of new inflammatory blood vessels that fail to develop mature physiological structure and functions[107-112]. Using transmission electron microscopy, a previous study examined these IMVECs and reported that they exhibit pathological alterations, including dilation of the endoplasmic reticulum, reduction in the number of ribosomes, rupture of the mitochondrial membrane, and absence of cristae[113]. Zhang et al[114] reported that IL-33-induced intestinal microvessels exhibit significantly increased permeability. Ardelean et al[115] observed increased density and hemodynamic activity in newly formed inflammatory blood vessels. Increased vascular density and permeability facilitate the extensive infiltration of circulating inflammatory cells into deep tissues, which in turn inhibit intestinal smooth muscle contractility[116]. Ardelean et al[115] also demonstrated that angiogenesis exacerbates both local intestinal and systemic inflammation, while anti-angiogenic therapy reduces the levels of inflammatory factors such as IL-1β, granulocyte colony-stimulating factor, C-C motif ligand 2, and hepatocyte growth factor, thereby attenuating intestinal inflammation. Greene et al[104] demonstrated that suppressing pathological angiogenesis by using cyclooxygenase-2 enzyme inhibitors significantly reduces the formation of intra-abdominal adhesions in mice. However, some scholars have proposed entirely opposite viewpoints. Langer et al[102] contend that angiogenesis is irrelevant to the pathogenesis of dextran sulfate sodium salt-induced colitis. In sum, pathological angiogenesis represents a dynamic and multifaceted contributor to intestinal inflammation and postoperative dysfunction. Its impact varies by context. Studies that integrate molecular signaling, vessel structure, perfusion dynamics, and immune cell trafficking are essential to define when and how angiogenesis should be targeted therapeutically.

Intestinal microcirculatory hemodynamic disturbances

Damaged endothelial cells release large amounts of vWF, rendering the blood hypercoagulable[43]. The vWF exposes binding sites and interacts with the glycoprotein Ib-IX-V complex on platelets and integrin αIIbβ3 to form aggregates[117]. These aggregates adhere to the damaged and activated IMVECs and serve as binding sites to further recruit leukocytes for adhesion[117]. The accumulation of platelet-leukocyte aggregates along with elevated inflammatory mediators increases blood viscosity and predisposes the blood to flow stasis[118]. Endothelial injury, a hypercoagulable milieu, and stasis act synergistically to promote microvascular thrombosis; when microthrombi organize into stable mural thrombi, local luminal stenosis can develop[118]. Blood flow through stenotic segments becomes turbulent, producing vortices and marked hemodynamic disturbance that can exacerbate barrier injury, local inflammation, and ileus[119-121]. Under mechanical stress, elevated expression of macrophage chemoattractant protein 1 induces macrophage adhesion and transendothelial migration and promotes the release of inflammatory mediators through activating the matrix metallopeptidase 9, NF-κB, and iNOS signaling pathways[41,122,123]. The combined induction effect of TNF-α and platelet-activating factors promotes leukocyte-platelet aggregation, leukocyte rolling adhesion, and firm endothelial adhesion[124]. Changes in shear stress also modulate endothelial signaling: High fluid shear activates the steroid receptor coactivator/extracellular regulated protein kinases axis, increasing matrix metalloproteinase expression and compromising barrier integrity[4,125]. In contrast, low fluid shear promotes the secretion of monocyte chemotactic protein 3, which binds CCR1 on macrophages and activates them through the transforming growth factor-β-activated kinase 1/NF-κB pathway[126]. Notably, however, clinical and experimental data are not entirely concordant: Zaidi et al[127] reported that accelerated capillary flow velocity did not correlate with inflammation severity in pediatric ulcerative colitis, underscoring the context- and model-dependence of hemodynamic-inflammatory relationships.

IMPROVING THE GVB FUNCTION: A NEW STRATEGY FOR PPOI TREATMENT

Dysfunction of IMVECs and the damage to the GVB are considered important pathological changes in PPOI. Therefore, improving the function of IMVECs and repairing the damaged GVB may be potential therapeutic targets for PPOI (Figure 5). Table 1 reviews drugs that can restore the GVB to improve PPOI.

Figure 5 Improving the function of intestinal microvascular endothelial cells and repairing the damaged gut vascular barrier as potential therapeutic targets for prolonged postoperative ileus. IL: Interleukin; eNOS: Endothelial nitric oxide synthase; MAPK: Mitogen-activated protein kinases; NF-kB: Nuclear factor kappa-B; AJ: Adherens junction; TJ: Tight junction; PPOI: Prolonged postoperative ileus; IMVEC: Intestinal microvascular endothelial cell. Created in BioRender (Supplementary material).

Table 1 Drugs for repairing the injured gut vascular barrier in prolonged postoperative ileus.

Drug	Mechanism	Biological activity	Animals/cells	Ref.
Kaempferol	Inhibiting the activation of inflammatory phenotype in IMVECs and strengthening the intestinal epithelial–endothelial barrier	Attenuating the overexpression of pro-inflammatory cytokines and adhesion molecules in IMVECs through inhibiting TLR4 overexpression and NF-κB, p38 MAPK, and STAT phosphorylation	RIMVECs	Bian et al[128], 2019; and Bian et al[133], 2020
Prostaglandin E2	Promoting the activity of IMVECs	Through the PGE2-EP4-eNOS signaling axis, prostaglandin E2 promotes IMVEC proliferation and NO production, which result in improved intestinal microcirculation	Mice/MIMVECs	Mo et al[129], 2023
Naringin	Inhibiting apoptosis, promoting cell migration, and upregulating the expression of endothelial cell junction proteins	Preventing TNF-α-induced apoptosis and migration suppression in IMVECs; Upregulating the expression of endothelial TJ, such as ZO-1, occludin, claudin-1, and claudin-2	RIMVECs	Liu et al[130], 2020
Quercetin	Protecting IMVECs from pyroptotic inflammation	Inhibiting the release of NLRP3 inflammasomes and the expression of pyroptotic proteins via the TLR4/NF-κB/NLRP3 signaling pathway to alleviate intestinal inflammation	Rat/RIMVECs	Zhang et al[131], 2022
Berberine	Reducing the permeability of the GVB	Increasing the expression of β-catenin, claudin-12, and VE-cadherin via modulating the Wnt/β-catenin pathway	Rat/RIMVECs	He et al[13], 2018
Dexmedetomidine	Reducing the permeability of the GVB	Increasing the expression of β-catenin, VE-cadherin, ZO-1, and occludin	Mice/MIMVECs	Zhang et al[61], 2022
Dihydroartemisinin	Repairing the intestinal epithelial–endothelial barrier	Increasing the expression of TJ and AJ and decreasing that of PV-1	Mice	Qiu et al[103], 2024
G6-31	Inhibiting angiogenesis; improving microcirculatory hemodynamics	Specifically binding to VEGF-A, inhibiting angiogenesis and improving microcirculatory hemodynamics	Mice	Ardelean et al[115], 2014
AP-Cav	Inhibiting angiogenesis	Inhibiting the proliferation of VECs and inducing VEC apoptosis through the suppression of the MAP signaling pathway and induction of JNK-dependent apoptosis	ECs	Fang and Kevil[135], 2020
N-palmitoyl-d-glucosamine	Inhibiting angiogenesis	Inhibiting the expression of inflammatory and pro-angiogenic factors by blocking the pAkt/mTOR/hypoxia-inducible factor1α pathway	Mice	Palenca et al[136], 2024
Heparin-binding epidermal growth factor-like growth factor	Improving intestinal microcirculation	Alleviating intestinal ischemia/reperfusion injury by reducing JNK phosphorylation and inhibiting the activation of the p38/MAPK signaling pathway Increasing the expression of the endothelin B receptor and triggering intracellular calcium mobilization	Rat/HIMVECs	Ming et al[138], 2019 and Zhou et al[139], 2009
Melatonin	Improving intestinal microcirculation	Attenuating pathological intestinal microvascular congestion and suppressing the infiltration of mast cells and granulocytes into intestinal tissues	Rat	Lansink et al[141], 2017

AJ: Adherens junction; GVB: Gut vascular barrier; IMVEC: Intestinal microvascular endothelial cell; PV-1: Plasmalemma vesicle-associated protein-1; TJ: Tight junction; TNF-α: Tumor necrosis factor-α; VEC: Vascular endothelial cell; VEGF: Vascular endothelial growth factor; eNOS: Endothelial nitric oxide synthase; MAPK: Mitogen-activated protein kinases; NF-kB: Nuclear factor kappa-B; NO: Nitric oxide; ZO-1: Zonula occludens-1; VE-cadherin: Vascular endothelial-cadherin; EC: Endothelial cell; RIMVEC: Rat intestinal microvascular endothelial cell; MIMVEC: Mouse intestinal microvascular endothelial cell; HIMVEC: Human intestinal microvascular endothelial cell.

Improving IMVEC function

IMVECs are the primary components of GVB and serve as trigger cells for inflammation. Suppression of the inflammatory phenotype activation in IMVECs and improving IMVEC function may effectively mitigate intestinal inflammation. Through the suppression of TLR4 overexpression and inhibition of NF-κB, p38 MAPK, and STAT phosphorylation, kaempferol attenuates lipopolysaccharide-induced overexpression of pro-inflammatory cytokines and adhesion molecules in IMVECs[128]. Prostaglandin E2 induces the phosphorylation of eNOS at Ser1177 by binding itself to the prostaglandin E2 receptor type 4 on IMVECs, which in turn stimulates IMVEC proliferation and NO production, ultimately improving intestinal microcirculatory function[129]. Naringin can prevent TNF-α-induced apoptosis and migration suppression in IMVECs, thereby maintaining the integrity of the GVB[130]. Quercetin inhibits the expression of inflammatory factors (IL-1β, IL-18, IL-6, and TNF-α) and pyroptotic proteins (caspase-1 and gasdermin D) via the TLR4/NF-κB/NOD-like receptor 3 signaling pathway, protecting IMVECs from pyroptotic inflammation[131].

Reducing the permeability of GVB

Increased GVB permeability facilitates the circulating immune cells to respond to local inflammatory signals and migrate across the endothelium[132]. Restoring the barrier function of the GVB may mitigate immune-inflammatory cell infiltration into the intestinal muscular layer in PPOI[50]. Reportedly, kaempferol enhances the GVB integrity by elevating transepithelial electrical resistance and upregulating TJ and AJ protein expression, thereby counteracting lipopolysaccharide-induced hyperpermeability[133]. In an inflammatory factor-induced GVB injury model, naringin has been shown to enhance the barrier function of GVB by increasing the expression and distribution of ZO-1, occludin, claudin-1, and claudin-2 proteins in IMVECs[130]. During sepsis, berberine protects the GVB and reduces microvascular leakage by regulating the Wnt/β-catenin signaling pathway and increasing the expression of β-catenin, claudin-12, and VE-cadherin[13]. In colitis models, dihydroartemisinin repairs the intestinal epithelial-endothelial barrier by increasing the expression of TJ and AJ and decreasing that of PV-1, ultimately ameliorating colonic inflammation[103]. Dexmedetomidine protects against GVB damage caused by intestinal ischemia-reperfusion by increasing the expression of β-catenin, VE-cadherin, ZO-1, and occludin[61].

Inhibiting pathological angiogenesis

Pathological angiogenesis is a hallmark of chronic intestinal inflammation. Therefore, inhibiting the aberrant proliferation of IMVECs and inflammatory angiogenesis may control the extent of infiltration by circulating leukocytes into the muscularis layer[134]. G6-31 is a monoclonal antibody with high affinity and specificity for VEGF-A. When colitis-afflicted mice were treated with G6-31, a significant reduction in intestinal microvascular density was observed (430 ± 24 mm^-2 vs 250 ± 26 mm^-2, P < 0.001)[115]. This reduction in microvessel density in colitis mice is accompanied by improved microvascular hemodynamics, decreased inflammatory cell infiltration into the muscular layer, and alleviated intestinal inflammation[115]. The anti-angiogenic effect of the antennapedia-conjugated caveolin-1 scaffolding domain is achieved through the suppression of the mitogen-activated protein signaling pathway and induction of c-Jun N-terminal kinase-dependent apoptosis, which inhibit the proliferation and promote the apoptosis of endothelial cells[135]. Micronized N-palmitoyl-d-glucosamine inhibits the expression of inflammatory and pro-angiogenic factors by blocking the pAkt/mammalian target of rapamycin/hypoxia-inducible factor 1α pathway, countering inflammatory angiogenesis in colorectal carcinoma[136].

Improving intestinal microcirculation

Surgical manipulation decreases the bowel wall perfusion by 29% and impairs intestinal motility[137]. Thus, we propose that improving intestinal microcirculation can improve intestinal motility. Heparin-binding epidermal growth factor-like growth factor can alleviate intestinal ischemia/reperfusion injury by reducing c-Jun N-terminal kinase phosphorylation and inhibiting the activation of the p38/MAPK signaling pathway[138]. Additionally, heparin-binding epidermal growth factor-like growth factor dilates the intestinal microvasculature and ameliorates intestinal microcirculation by increasing the expression of endothelin B receptor and provoking intracellular calcium mobilization[139]. Inflammation leads to increased intestinal microvascular hemodynamics and induces vascular inflammation. Anti-VEGF therapy can decrease intestinal microvascular hemodynamics and vascular inflammation, resulting in reduced intestinal inflammation[115]. Necrotizing enterocolitis leads to impaired intestinal microcirculatory perfusion. Promotion of endogenous NO and production of hydrogen sulfide through remote ischemic conditioning have been proven to maintain intestinal microcirculatory perfusion and reduce the ischemic necrosis of intestinal villi[140]. Intestinal congestion, edema, and hemorrhage are adaptive changes in response to inflammation. Using murine models of systemic inflammation, it has been shown that intravenous melatonin attenuates pathological intestinal microvascular congestion and suppresses the infiltration of mast cells and granulocytes into intestinal tissues[141].

CONCLUSION

PPOI is one of the most common postoperative complications, especially after abdominal surgery. In PPOI, both local inflammation and vascular inflammation mutually reinforce each other, triggering a cascade of events that disrupts the intestinal barrier, impairs intestinal neuronal conduction, and inhibits intestinal contractile activity. IMVEC dysfunction, increased GVB permeability, pathological angiogenesis, and intestinal microcirculatory hemodynamic alterations are the fundamental pathological alterations in PPOI. Thus, the GVB may present a potential therapeutic target for PPOI. Improving IMVEC function, reducing GVB permeability, inhibiting pathological angiogenesis, and improving intestinal microcirculation are highly likely to shorten or even block the progression of PPOI. However, further in vivo and in vitro studies are required to substantiate this hypothesis.