Boswellic acid inhibits inflammatory angiogenesis in a murine sponge model Sarita Saraswati, Maneesha Pandey, Rajani Mathur, S.S. Agrawal ⁎ Genome Research Laboratory, Delhi Institute of Pharmaceutical Sciences and Research, Pushp Vihar Sec-3, M B Road, New Delhi-110017, India abstract article info Article history: Accepted 5 August 2011 Available online 12 August 2011 The aim of the present study was to investigate the effects of boswellic acid (BA) on key components of inflammatory angiogenesis in the murine cannulated sponge implant angiogenesis model. Polyester– polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and BA (12.5 or 25 mg/kg/day) was given through installed cannulas for nine days. The implants collected at day 9 post-implantation were processed for the assessment of hemoglobin (Hb). Relevant levels of inflammatory, angiogenic and fibrogenic cytokines were also determined. BA treatment resulted in significant decrease in sponge vascularization (Hb content) and in vascular endothelial growth factor (VEGF) and transforming growth factor (TGF-β1) at both doses. Further, BA decreased expression of VEGF and CD31 and reduced % microvessel density (MVD) in sponge implants. A regulatory function of BA on multiple parameters of the main components of inflammatory angiogenesis has been revealed giving an insight into the potential therapeutic use underlying the actions of BA. © 2011 Elsevier Inc. All rights reserved. Introduction Angiogenesis and inflammation are persistent features of several pathological conditions such as rheumatoid arthritis, cancer, psoriasis, and atherosclerosis. Inflammation is responsible for a substantial portion of tumor vascularization referred to as “inflammatory angiogenesis,” with leukocytes acting as angiogenesis initiators. Chemoprevention has recently focused on angiogenesis, as the role of direct mediators of angiogenesis secreted by tumor cells to interrupt the carcinogenic process (Folkman, 1971). By blocking the neovascularization before the angio- genic switch point, chemopreventive anti-inflammatory approach will result in a significant delay in development of clinically relevant cancer (Alibini et al., 2005). The mechanisms of inflammatory angiogenesis provide new approaches to target, cure and prevent tumor angiogenesis by treatment using synthetic or natural agents with anti-inflammatory properties. Boswellic acid is isolated from Boswellia serrata, (also known as Salai guggul). Boswellic acid (BA) has been used to treat Crohn disease, ulcerative colitis, bronchial asthma, endotoxin induced hepatitis and arthritis (Sharma et al., 1989; Safayhi et al., 1991; Gupta et al., 1997; 1998; 2001; Gerhardt et al., 2001; Kiela et al., 2005). Boswellic acid (BA) is a mixture composed of four major pentacyclic triterpene acids: beta-boswellic acid, 3-acetyl beta boswellic acid, 11-keto-beta-boswellic acid and 3-acetyl-11-keto-beta-boswellic acid, and has been reported to be effective as an anti-inflammatory (Singh and Atal, 1986), immuno- modulatory (Sharma et al., 1996) and anti-asthmatic (Gupta et al., 1998) agent. It has been found to inhibit leukotriene synthesis via the 5- lipoxygenase and cycloxygenase pathways (Ammon et al., 1993), the key enzyme for leukotriene biosynthesis in inflammatory disorders (Safayhi et al., 1992; Sailer et al., 1996) and human leukocyte elastase (Safayhi et al., 1997). Besides its renowned anti-inflammatory activity, BA has been investigated with respect to its activity against tumor cells and its chemopreventive effects (Glaser et al., 1999; Zhao et al., 2003). Previous studies have reported that BA possesses cytostatic, anti-apoptotic, anti- tumor (Huang et al., 2000) and anti-angiogenic activities (Hostanska et al., 2002; Lu et al., 2008; Singh et al., 2007). For instance, BA inhibited cellular proliferation and induced apoptosis in brain tumor (Glaser et al., 1999; Winking et al., 2000; Park et al., 2002), leukemia (Han, 1994; Shao et al., 1998; Hoernlein et al., 1999; Jing et al., 1999), melanoma, hepatoma and prostate cancer cell lines in vitro (Liu et al., 2002; Zhao et al., 2003; Syrovets et al., 2005). In spite of these therapeutic effects of BA, little is known about its anti- angiogenic potential. In this study, we have used the murine cannulated sponge implant angiogenesis model to investigate its effect on inflam- matory angiogenesis. Materials and methods Animals Five to six weeks old (20–30 g body weight) male Swiss albino mice were obtained from the Central Animal Facility at Delhi institute of Pharmaceutical Sciences and Research, India. The animals were housed individually in plastic cages and allowed access to a normal diet and water Microvascular Research 82 (2011) 263–268 ⁎ Corresponding author at: Genome Research Laboratory, Delhi Institute of Pharma- ceutical Sciences and Research, Pushp Vihar Sec-3, M B Road, New Delhi-110017, India. Fax: +91 29554503. E-mail addresses: saritasaraswati@gmail.com (S. Saraswati), ssagrawal1946@gmail.com (S.S. Agrawal). 0026-2862/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.mvr.2011.08.002 Contents lists available at SciVerse ScienceDirect Microvascular Research journal homepage: www.elsevier.com/locate/ymvre