Send Orders of Reprints at reprints@benthamscience.org Current Pharmaceutical Design, 2013, 19, 17-28 17 Novel Pharmacologic Approaches to the Prevention and Treatment of Ulcerative Colitis Xiaoming Deng a,c , Sandor Szabo a,c,d , Tetyana Khomenko a,c , Ganna Tolstanova a,c,g , Brankica Paunovic a , Samuel W. French f and Zsuzsanna Sandor b,e,* a Pathology & Laboratory Medicine Service, and b Primary Care & Specialty HCG, VA Long Beach Healthcare System; and Depart- ments of c Pathology, d Pharmacology & e Medicine, University of California-Irvine, Long Beach, CA; f Harbor-UCLA Medical Center, Los Angeles, CA, USA; g Department of Pharmaco-Physiology, Kiev National Shevchenko University, Kiev, Ukraine 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 be- fore 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 evi- dences from us and others indicate that angiogenesis plays a pathogenic role in UC, e.g., VEGF induces an abnormal “pathologic” angio- genesis 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 angiogene- sis 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 in- creased 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 pro- gression of UC. In this review, we discuss novel pharmacologic approaches to prevent UC, differential actions of angiogenic growth factors in UC patho- genesis and blocking the early increase in VP in UC development, these new findings may provide new insights into the regulation of an- giogenesis 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. INTRODUCTION Ulcerative colitis (UC) is a chronic and recurring disease with a major clinical and economic impact and its incidence is growing. In UC, the ulcers are surrounded by acute (e.g., neutrophils) and/or chronic (e.g., lymphocytes, plasma cells, macrophages) inflamma- tory cells, hence often leading to the mistaken pathogenic target of treating UC by anti-inflammatory drugs to suppress the secondary inflammatory response to the previously induced ulcerative lesions. For unknown reasons, nevertheless, UC often leads to carcinomas [1,2]. Although recent studies on mechanisms of chronic inflamma- tory components of UC have brought progress in UC therapy, cur- rent anti-TNF antibody (infliximab) and other anti-inflammatory treatment (e.g., mesalamine) induced sustained clinical long term remission at 52 weeks in fewer than 34% of patients [3-5]. This means that in the majority of patients these treatments do not induce sustained remission and complete healing or prevent recurrence. The healing aspects of UC and the mechanisms governing the heal- ing component of UC have not been explored in depth and are not well understood. Thus, research is needed to address our current lack of understanding of how UC are triggered, why it easily recurs, and what the precise cellular and molecular targets are for complete and permanent healing. *Address correspondence to this author at the VA Medical Center (05/113), 5901 East 7 th Street, Long Beach, CA 90822, USA; Tel: 562-826-5513; Fax: 562-826-5768; E-mail: zsuzsanna.sandor@va.gov The main focus of our research laboratory has been the vascular elements of gastrointestinal (GI) mucosal injury and healing. Long before angiogenesis became a popular term and research topic, we proposed that growth of new capillaries from existing blood vessels surrounding the ulcer crater is a rate-limiting step in ulcer healing. Stimulation of angiogenesis leads to development of granulation tissue that is essential for the healing process. Our earlier studies demonstrated that therapy with genes or peptides of angiogenic factors such as basic fibroblast growth factor (bFGF), platelet- derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), significantly accelerated healing of experimental duodenal ulcers (DU), while blockade of these angiogenic factors resulted in impaired healing of DU [6-9]. Since histologically and pathologically gastroduodenal ulcers look similar to ulcers in the lower GI tract, we also predicted that the healing of UC might be also improved by stimulating angiogenesis. However, recent data of ours and others showed that angiogenic therapy targeting VEGF aggravated healing of experimental UC but anti-VEGF treatment improved the healing [10,11]. Increasing evidences indicate that VEGF induces pathologic “abnormal” angiogenesis that links in- flammation and plays a pathogenic role in experimental UC [12,13]. However, it has been reported that anti-VEGF therapy often results in gastric ulcer perforation and skin ulcers in patients [14,15] as anti-VEGF may also affect physiologic angiogenesis needed in tissue repair and organ regeneration. Thus, it is important to recognize the inducers and modulators of pathologic angiogene- sis. Recently, placental growth factor (PlGF) has been identified as a marker of pathologic angiogenesis and may play a specific role in 1873-4286/13 $58.00+.00 © 2013 Bentham Science Publishers