α5β1 Integrin Blockade Inhibits Lymphangiogenesis in Airway Inflammation

Abstract

The integrin ␣5␤1 has been previously implicated in tumor angiogenesis, but its role in the remodeling of both blood vessels and lymphatics during inflammation is at an early stage of understanding. We examined this issue using a selective, small-molecule inhibitor of ␣5␤1 integrin, 2-aroylamino-3-{4-[(pyridin-2-ylaminomethyl)heterocyclyl]phenyl}propionic acid (JSM8757), in a model of sustained airway inflammation in mice with Mycoplasma pulmonis infection, which is known to be accompanied by robust blood vessel remodeling and lymphangiogenesis. The inhibitor significantly decreased the proliferation of lymphatic endothelial cells in culture and the number of lymphatic sprouts and new lymphatics in airways of mice infected for 2 weeks but did not reduce remodeling of blood vessels in the same airways. In inflamed airways, ␣5 integrin immunoreactivity was present on lymphatic sprouts, but not on collecting lymphatics or blood vessels, and was not found on any lymphatics of normal airways. Macrophages, potential targets of the inhibitor, did not have ␣5 integrin immunoreactivity in inflamed airways. In addition, macrophage recruitment, assessed in infected airways by quantitative reverse transcription-polymerase chain reaction measurements of expression of the marker protein ionized calcium-binding adapter molecule 1 (Iba1) , was not reduced by JSM8757. We conclude that inhibition of the ␣5␤1 integrin reduces lymphangiogenesis in inflamed airways after M. pulmonis infection because expression of the integrin is selectively increased on lymphatic sprouts and plays an essential role in lymphatic growth.

Endothelial α5 and αv integrins cooperate in remodeling of the vasculature during development

“…For example, 51 integrin has been implicated in tumor angiogenesis (Taverna and Hynes, 2001) and has been found to be upregulated in vivo in a cerebral hypoxia model (Milner et al, 2008). In addition, developmental lymphangiogenesis seems to be unaffected, in contrast to a recent study showing that 51 blockade affects pathological lymphangiogenesis (Okazaki et al, 2009). Therefore, it would be interesting to test the role of endothelial 5 integrin in pathological models of angiogenesis, in order to validate endothelial cells as targets for the blocking reagents in those models.…”

Deletion of Tetraspanin CD9 Diminishes Lymphangiogenesis in Vivo and in Vitro

“…It has also been shown that ␣9 integrin binds VEGF-C directly (13). Moreover, inhibition of ␣5␤1 integrin reduced lymphangiogenesis in inflamed airways after Mycoplasma pulmonis infection and in corneal inflammation (14,15). Recent papers also suggest that VEGFR-3 forms complexes with integrins, such as ␤1 and ␣5 in lymphatic endothelial cells (LEC) (16,17).…”

Integrin α9 on lymphatic endothelial cells regulates lymphocyte egress

“…S2). This process is regulated by several factors including integrins (9)(10)(11)(12)(13). In this study, we found that α9-mediated signaling is dispensable for CFA-induced lymphangiogenesis (Fig.…”

“…Factors, including vascular endothelial growth factor receptor 3 (VEGFR3), lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), transcription factor prox-1, and integrins, regulate lymphatic vessel growth and development (9)(10)(11)(12)(13). Among the integrins, α9 integrin (α9 hereafter) is critical for the development of lymphatic valves (14,15).…”