Inhibition of granuloma‐associated angiogenesis by controlling mast cell mediator release: role of mast cell protease‐5

Abstract

1 We investigated the role of mast cells in granuloma-associated angiogenesis in rat by using: (i) a mast cell membrane stabilizer, ketotifen; (ii) a mast cell depleting agent, compound 48/80. Moreover, we focused on the role of chymases, which exhibit proinflammatory and proangiogenic properties by using: (i) chymostatin, an inhibitor of chymase activity; (ii) a specific antisense oligonucleotide (AS-ODN) designed against rat mast cell protease-5 (rMCP-5), the most abundantly expressed chymase in the skin. 2 The formation of granuloma was evaluated, as wet weight, 96 h after the subcutaneous implant of two l-carrageenin (1%)-soaked sponges on the back of male Wistar rats. Angiogenesis was evaluated as haemoglobin content in the granulomatous tissue and as level of tumour necrosis factor-a (TNF-a) in the exudates. 3 A single injection of ketotifen (1-5-25 mg kg À1 i.p.) significantly reduced granuloma formation by 31.6, 44.6 and 71.9%, and haemoglobin content by 17.0, 35.0 and 66.2%, suggesting that the release of mediator(s) from mast cells modulates the process. Chymostatin (5-10 nmol À1 site À1 day À1 ) reduced granuloma-associated angiogenesis by 57.3 and 70.0%. 4 RT-PCR analysis showed that rMCP-5 mRNA amounts were significantly reduced by rMCP-5 AS-ODN (1.25-2.5-5.0 nmol site À1 ) by 69.5, 72.5 and 81.8%. In parallel experiments, rMCP-5 AS-ODN (1.25, 2.5, 5.0 nmol site À1 ) strongly reduced granuloma weight (26.1, 45.0 and 56.3%) and haemoglobin content (22.2, 50.4, 62.03%), suggesting that the observed effect is mediated through an antisense mechanism. 5 In conclusion, these data suggest that: (i) inhibition of mast cell mediators release may represent a novel strategy to modulate angiogenesis; (ii) among the chymase family, rMCP-5 is a key promoter of angiogenesis in the rat.

Mast cells associate with neovessels in the media and adventitia of abdominal aortic aneurysms

“…Animal studies have shown that neovascularization is reduced in MC-deficient mice, and granuloma-associated neovascularization can be inhibited by controlling MC activation. 27 MC-derived histamine upregulates c-jun expression and c-jun N-terminal kinase (JNK) activity, 28 and increased JNK activity seems to promote aneurysm formation. 29 In addition, MCs may promote chemotaxis of inflammatory cells into the AAA wall by inducing ET-1 expression.…”

Effects of myrrh on intra-oral mucosal wounds compared with tetracycline- and chlorhexidine-based mouthwashes

“…[3][4][5]11,12 It has also been shown to stimulate plasma cell production and induce angiogenesis and, therefore, remodeling within 7 days of an injury occurring. 27,28 Accordingly, myrrh may be potentially useful in the induction of wound healing and repair.…”

Interferon γ-Induced Human Guanylate Binding Protein 1 Inhibits Mammary Tumor Growth in Mice

“…To determine the qualitative capacity of the newly formed tumor vessels to supply the respective tissue with oxygen and nutrients, the amount of hemoglobin was determined in tumors with and without hGBP-1 expression ( Figure 5B). This well-established method is applied to quantify the actual state of perfusion within a given tumor tissue (34,35). For each group of tumors, 18 samples were analyzed.…”