Development of Pial Collaterals by Extension of Pre-existing Artery Tips

SUMMARY Pial collaterals provide protection from ischemic damage and improve prognosis of stroke patients. The origin or precise sequence of events underlying pial collateral development is unclear and has prevented clinicians from adapting new vascularization and regeneration therapies. We use genetic lineage tracing and intra-vital imaging of mouse brains at cellular resolution to show that during embryogenesis, pial collateral arteries develop from extension and anastomoses of pre-existing artery tips, in a VegfR2 dependent manner. This process of artery tip extension occurs on pre-determined microvascular tracks. Our data demonstrate that an arterial receptor, Cxcr4, earlier shown to drive artery cell migration and coronary collateral development, is dispensable for formation and maintenance of pial collateral arteries. Our study shows that collateral arteries of the brain are built by a unique mechanism, distinct from that of the heart.