Early‐phase cerebral arteriogenesis: Evidence of endothelial activation, vascular proliferation and local inflammation

Arteriogenesis holds potential as a novel treatment for ischemic vascular disease. Our study aimed at an identification of key processes of early‐phase cerebral arteriogenesis in vivo. In a rat model of nonischemic cerebral hypoperfusion the posterior cerebral artery (PCA) constitutes a main collateral to the contralateral hemisphere. Following reversed flow, endothelial cell (EC) activation was assessed by electron microscopy. Gene expression during biomechanical EC activation was analyzed by cDNA microarray. Proarteriogenic vascular proliferation and local inflammation were evaluated. PCA diameters increase significantly(+30%). Ultrastructural EC activation occurs at 3d postoperatively, followed by CD68+ cellular transmigration and sustained vessel wall proliferation. Of 164 genes deregulated, 48 contain shear stress response elements (SSREs) or NFkB binding sites in their promoter regions. Arteriogenesis leads to NFkB activation as shown by local NFkB p65 expression. Cerebral arteriogenesis is initiated by EC activation through changed blood flow, facilitating monocyte influx and collateral proliferation. Gene expression is modified by biomechanical activation via SSREs and the pro‐inflammatory environment (NFkB activation, monocyte influx). Therapeutic arteriogenesis may aim at 1) biomechanical EC activation 2)vascular proliferation or 3)local monocyte function.