Novel Pharmacologic Approaches to the Prevention and Treatment of Ulcerative Colitis

Xiaoming      Deng; Sandor      Szabo; Tetyana      Khomenko; Ganna      Tolstanova; Brankica      Paunovic; Samuel      W. French; Zsuzsanna      Sandor

doi:10.2174/1381612811306010017

Abstract

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colonic mucosa followed by poor quality of healing and recurring lesions. Recent studies demonstrated that the poor healing and chronic inflammation in colon of UC could be the result of microvascular dysfunction and endothelial barrier defect, resulting in sustained tissue hypoperfusion and ischemia in the colon. Long before angiogenesis became a popular research topic, our laboratory was the first to postulate that stimulation of angiogenesis alone might be sufficient to accelerate ulcer healing in the gastrointestinal tract. Our earlier studies demonstrated that therapy with genes or peptides of angiogenic growth factors, e.g., bFGF, PDGF and VEGF significantly accelerated healing of experimental duodenal ulcers (DU), while blockade of these angiogenic factors resulted in impaired healing of DU. However, unlike the angiogenesis in DU, increasing evidences from us and others indicate that angiogenesis plays a pathogenic role in UC, e.g., VEGF induces an abnormal “pathologic” angiogenesis which interferes with UC healing. Recently, another angiogenic factor, placental growth factor (PlGF), has also been suggested to be a marker of pathologic angiogenesis and may play a critical role in pathogenesis of UC. Although inhibition of pathologic angiogenesis by, e.g., anti-VEGF or –PlGF, was demonstrated to be a new approach to attenuate UC development, additional data of our and others showed that stimulating angiogenesis by administration of PDGF or bFGF significantly accelerated healing of UC. Also, activation of Rac1, a small GTPase, markedly improved VEGF-induced neovessel architecture defect and reduced vascular permeability (VP) in an angiogenic model. Thus, it seems that both angiogenic and anti-angiogenic therapies may be used in various stages of UC. More recently, we demonstrated that increased VP in colonic mucosa is an early and essential element in the initiation and progression of UC. The increased VP is initiated by early release of histamine and maintained/aggravated by VEGF, leading to perivascular edema, vascular stasis, hypoxia, inflammatory cell infiltration, and colonic erosions/ulcers. Inhibition of increased VP prevents or reduces development and progression of UC.

In this review, we discuss novel pharmacologic approaches to prevent UC, differential actions of angiogenic growth factors in UC pathogenesis and blocking the early increase in VP in UC development, these new findings may provide new insights into the regulation of angiogenesis in UC and may lead to development of VP-related drugs to accelerate the healing of UC.

Keywords: Angiogenesis, angiogenic growth factors, bFGF, PDGF, VEGF, PlGF, Rac-1, pathologic angiogenesis, histamine, Src kinase, VE-cadherin, vascular permeability, ulcer healing, ulcerative colitis