Differential Angiogenic Regulation of Experimental Colitis

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders of the intestinal tract with unknown multifactorial etiology that, among other things, result in alteration and dysfunction of the intestinal microvasculature. Clinical observations of increased colon microvascular density during IBD have been made. However, there have been no reports investigating the physiological or pathological importance of angiogenic stimulation during the development of intestinal inflammation. Here we report that the dextran sodium sulfate and CD4+CD45RBhigh T-cell transfer models of colitis stimulate angiogenesis that results in increased blood vessel density concomitant with increased histopathology, suggesting that the neovasculature contributes to tissue damage during colitis. We also show that leukocyte infiltration is an obligatory requirement for the stimulation of angiogenesis. The angiogenic response during experimental colitis was differentially regulated in that the production of various angiogenic mediators was diverse between the two models with only a small group of molecules being similarly controlled. Importantly, treatment with the anti-angiogenic agent thalidomide or ATN-161 significantly reduced angiogenic activity and associated tissue histopathology during experimental colitis. Our findings identify a direct pathological link between angiogenesis and the development of experimental colitis, representing a novel therapeutic target for IBD.

Absence of placental growth factor blocks dextran sodium sulfate-induced colonic mucosal angiogenesis, increases mucosal hypoxia and aggravates acute colonic injury

“…Danese et al 2 found that the anti-angiogenic compound ATN-161, a dual AVb3/5b1 inhibitor, has convincing therapeutic effects in the chronic IL10 -/-colitis model. The same benefit was seen by Chidlow et al 26 in the CD4 þ CD45RBhigh model. However, ATN-161 had no therapeutic action in DSS-induced colitis.…”

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

“…Increased microvascular density in CD and UC has been shown clinically, and our work corroborates this through PECAM-1/CD31 staining of the microvasculature in CD specimens where vessel density is significantly increased in the mucosal and submucosal tissue layers with a total increase in vascular density being similar to that observed in experimental colitis (Fig. 2) (31,58,92,143). Interestingly, microvascular dysfunction during IBD shows a temporal relationship with tissue pathology based on observed microscopic alterations in tissue morphology (95).…”

“…Our laboratory has recently determined that differential regulation of pro-vs. antiangiogenic gene expression dictates this phenomenon by creating imbalances between these regulatory factors (i.e., upregulation of pro-over antiangiogenic factors or relative downregulation of antiangiogenic factors) (31). Evidence indicates that some of the upregulated angiogenic factors involved in colitis may prevent the maturation of vessels, contributing to the pathological nature of this angiogenesis.…”

“…Development of new vasculature during chronic inflammation may play a negative "pathological" role by contributing to increased inflammatory responses due to dysfunctional new vessel architecture and increases in the recruitment of inflammatory cell types. Importantly, recent data have shown that angiogenic inhibition during chronic inflammatory diseases attenuates further inflammation and disease pathology (31,37,51). As such, expanding our knowledge of how pathological angiogenesis occurs during IBD will further our ability to treat patients with these diseases.…”

“…It has been suggested that the angiogenic components of these diseases contribute to and exacerbate disease conditions (26, 31). Recent findings, both clinical and experimental, indicate that angiogenesis also plays a crucial role in the inflammatory bowel diseases (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC) (31,37,58,131,155). Development of new vasculature during chronic inflammation may play a negative "pathological" role by contributing to increased inflammatory responses due to dysfunctional new vessel architecture and increases in the recruitment of inflammatory cell types.…”