The Role of Monocytes/Macrophages and Vascular Resident Precursor Cells in Collateral Growth

Macrophage accumulation is a hallmark of early collateral development and coincides with maximal vascular proliferation and main rise in collateral conductance. Enhancement of macrophage recruitment promoted collateral growth. Yet the precise role of these cells and their origin remained enigmatic. We originally proposed that elevation of shear forces in pre-existing arteriolar anastomoses promotes monocyte homing and macrophage accumulation. Shear force, however, inhibits monocyte recruitment via upregulation of NO and downregulation of cell adhesion molecules. Based upon recent studies we present 2 possible resolutions: 1. Shear forces and expression of NO donating enzymes were initially down-regulated in collateral arteries allowing recruitment of circulating cells. 2. Furthermore we detected a regenerative subadventitial zone in arterial vessels containing CD 34 positive progenitor cells as main source of macrophages and vascular cells during collateral growth. We thus propose following sequence of events: Hemodynamic changes in preexisting arteriolar shunts lead to activation, proliferation and differentiation of progenitor cells situated in the subadventitial space supplying the cellular components for collateral remodeling. The local pool of progenitor cells is replenished by circulating cells during the very initial phase of collateral growth when due to acute rises in peripheral resistance shear force is lowered. The following remodeling phase of collateral growth occurs in the absence of marked macrophage accumulation and is mainly perpetuated by the differentiation and migration of cells from the existing pool. This new paradigm lowers the importance of acute homing processes and focuses our attention onto local activation of vascular resident progenitor cells as therapeutic target