Title : In sickness and in health: Delineating the roles of angiopoietin-2 in physiological and pathological conditions
Abstract:
Lymphangiogenesis is a fundamental physiological process that also contributes significantly to the development and progression of vascular related pathological conditions. Angiopoietin-2 (Ang2) is a key regulator of lymphatic vascular development and function, and elevated Ang2 expression has been reported in several vascular-associated diseases, including cancer. Here, we demonstrate that Ang2-induced migration of human dermal lymphatic endothelial cells is mediated by the small GTPase RhoA. We further show that this migratory response occurs independently of Tie receptors and instead relies on β1 integrin-dependent activation of RhoA, and we characterize the downstream signaling pathway involved. The functional relationship between Ang2 and RhoA was also investigated in vivo, where lymphatic endothelial-specific RhoA deficiency impaired Ang2-induced lymphangiogenesis, identifying RhoA as a potential therapeutic target for anti-lymphangiogenic strategies. Finally, to investigate the contribution of tumor-derived Ang2 to tumor development, we used CRISPR-Cas genome editing to reduce Ang2 expression in tumor cells and assessed the effects of Ang2 deficiency on tumor cell behavior, tumor growth, and features of the tumor microenvironment
