Role of PECAM-1 in Arteriogenesis and Specification of Preexisting Collaterals

Abstract

Hemodynamic forces caused by the altered blood flow in response to an occlusion lead to the induction of collateral remodeling and arteriogenesis. Previous work showed that platelet endothelial cell adhesion molecule (PECAM)-1 is a component of a mechanosensory complex that mediates endothelial cell responses to shear stress. We hypothesized that PECAM-1 plays an important role in arteriogenesis and collateral remodeling. PECAM-1 knockout (KO) and wild-type littermates underwent femoral artery ligation. Surprisingly, tissue perfusion and collateral-dependent blood flow were significantly increased in the KO mice immediately after surgery. Histology confirmed larger caliber of preexisting collaterals in the KO mice. Additionally, KO mice showed blunted recovery of perfusion from hindlimb ischemia and reduced collateral remodeling, because of deficits in shear stress-induced signaling, including activation of the nuclear factor κB pathway and inflammatory cell accumulation. Partial recovery was associated with normal responses to circumferential wall tension in the absence of PECAM-1, as evidenced by the upregulation of ephrin B2 and monocyte chemoattractant protein-1, which are 2 stretch-induced regulators of arteriogenesis, both in vitro and in vivo. Our findings suggest a novel role for PECAM-1 in arteriogenesis and collateral remodeling. Furthermore, we identify PECAM-1 as the first molecule that determines preexisting collateral diameter.