MIP‐2 activates AKT and RhoA in mouse aortic endothelial cells

Abstract

ELR+ CXC chemokines are potent promoters of angiogenesis and have been shown to induce chemotaxis in endothelial cells (ECs). We reported previously that EC chemotaxis was markedly enhanced in systemic arterial ECs compared to pulmonary artery ECs in response to MIP-2, a potent proangiogenic ELR+ CXC chemokine ligand, which binds the G-protein coupled receptor, CXCR2. Also, we previously showed equivalent levels of CXCR2 expression in the two EC subtypes. However, differences in EC motility in response to MIP-2 may depend on differential utilization of signaling pathways. We studied the roles of protein kinase B/AKT and small GTPase RhoA in MIP-2 activation of mouse aortic (n=4) and pulmonary artery (n= 3) ECs. Additionally, since tissue hypoxia increases the angiogenic potential of systemic ECs, we studied ECs after hypoxia (24hrs)/reoxygenation (48hrs). MIP-2 (30min, 10 ng/ml) induced a greater increase in AKT phosphorylation (pAKT) in aortic ECs (33%) compared to pulmonary artery ECs (17%). Hypoxia/reoxygenation increased pAKT in aortic ECs (46%) but did not alter pulmonary artery EC pAKT. Only aortic ECs showed an increase in RhoA activation (40%) after MIP-2 treatment and hypoxia/ reoxygenation further increased RhoA activation after MIP-2 in aortic ECs (71%). These results confirm that AKT and RhoA are involved in MIP-2 induced activation of a proangiogenic phenotype, preferentially in aortic ECs. Supported by HL71605