Anti-vascular Endothelial Growth Factor Therapy in Mouse Models of Vascular Dysplasia and Chronic Colitis

Hereditary hemorrhagic telangiectasia (HHT) and inflammatory bowel disease (IBD) are associated with pathological angiogenesis. Vascular endothelial growth factor, VEGF, is a major angiogenic modulator implicated in HHT and IBD. Hence, we hypothesized that VEGF-targeted therapy might be beneficial in these disorders. HHT is an inherited vascular dysplasia characterized by arteriovenous malformations in organs leading to severe complications. HHT is caused by mutations in Endoglin (ENG; HHT1) or Activin receptor-like kinase 1 (ALK1; HHT2) genes, coding for transforming growth factor (TGF-) superfamily receptors. We studied the angiogenic phenotype of Endoglin and Alk1 heterozygous mice and determined their response to anti-VEGF therapy. We demonstrated that lungs, but not liver, heart or colon, showed dysregulated angiogenesis, characterized by reduction in peripheral microvessel density (MVD). An increase in angiostatic thrombospondin-1 (TSP-1) and vascular destabilizing factor angiopoietin-2 (Ang-2), was associated with reduced MVD in Eng+/- and Alk1+/- lungs respectively. Surprisingly, anti-VEGF treatment increased peripheral pulmonary MVD and normalized levels of TSP-1 and Ang-2, suggesting that the treatment restored the angiogenic balance by distinct pathways in HHT1 and HHT2 models. IBD is characterized by severe, relapsing gut inflammation, leading to multiple complications. Pathological angiogenesis in chronic colitis is persistent, excessive and abnormal. We tested the effect of anti-VEGF therapy in chronic colitis using the Eng+/- mouse model subjected to dextran-sodium sulphate, characterized by severe, chronic intestinal inflammation and pathological angiogenesis. We demonstrated that pathologic angiogenesis is characterized by high colonic MVD and increased in vivo microvascular hemodynamics, as assessed by ultrasound. Interestingly, colitic Eng+/- mice showed an inflammation-induced rise in colonic endoglin, several pro-inflammatory cytokines and myeloid chemotactic factors. They had a further increase in G-CSF and amphiregulin, when compared to wild type mice. This suggests that endoglin might have a triple role, as a protective regenerative factor and as a marker of inflammation and angiogenesis in colitis. Importantly, anti-VEGF therapy showed effects associated with resolution of in vivo and in vitro inflammation and pathological angiogenesis in the Eng+/- model of chronic colitis. Our findings establish the foundation for future translational studies in patients with vascular dysplastic and chronic inflammatory diseases.Ph.D.2017-06-14 00:00:0