Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a Jack of all trades

Abstract

The etiology of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD), is still largely unknown. However, it is now clear that the abnormalities underlying pathogenesis of intestinal inflammation are not restricted to those mediated by classic immune cells but also involve nonimmune cells. In particular, advances in vascular biology have outlined a central and multifaceted pathogenic role for the microcirculation in the initiation and perpetuation of IBD. The microcirculation and its endothelial lining play a crucial role in mucosal immune homeostasis through tight regulation of the nature and magnitude of leukocyte migration from the intravascular to the interstitial space. Chronically inflamed IBD microvessels display significant alterations in microvascular physiology and function compared with vessels from healthy and uninvolved IBD intestine. The investigation into human IBD has demonstrated how endothelial activation present in chronically inflamed IBD microvessels results in a functional phenotype that also includes leakiness, chemokine and cytokine expression, procoagulant activity, and angiogenesis. This review contemplates the newly uncovered contribution of intestinal microcirculation to pathogenesis and maintenance of chronic intestinal inflammation. In particular, we assess the multiple roles of the microvascular endothelium in innate immunity, leukocyte recruitment, coagulation and perfusion, and immune-driven angiogenesis in IBD.

Figure 1

The role of microvasculature in the pathogenesis of inflammatory bowel disease. 1. Leukocyte-endothelium interaction: The chronically inflamed endothelium displays enhanced leukocyte binding capacity and up-regulation of adhesion molecules. 2. Innate immunity: Pattern recognition receptors contribute to the activation of intestinal endothelium, increasing leukocyte adhesion and transmigration and contributing to the cytokine network of the gut mucosa. 3. Hypercoaguability: In IBD, a hypercoagulable state and a prothrombotic condition exist; in particular, the impairment of expression and function of the PC pathway and the overexpression of tissue factor suggest the biological importance of coagulation cascade and its alterations in intestinal inflammation. 4. Platelet activation: The intimate adherence of platelets to the endothelium is characteristic of IBD, and it is well established that platelets behave aberrantly in both UC and CD. 5. Endothelial dysfunction: Intrinsic alterations in the chronically inflamed and remodeled microcirculation underlie vascular dysfunction that seems to play a fundamental role in chronic, deregulated inflammation, which characterizes IBD. 6. Angiogenesis: The enhancement of angiogenesis in IBD highlights neovascularization as a major contributor to the initiation and perpetuation of chronic intestinal inflammation.