The VEGF Pathway, CLIC4, and the Development of the Collateral Circulation (2012)

Undergraduate: Jeff Morrison

Faculty Advisor: Jennifer Lucitti
Department: Biology

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Collateral arteries directly link two opposing arterial trees and are found in many tissues, including the brain, heart, and peripheral limbs. They have no clear function during normal circulation but become critical bypass vessels after vascular obstruction (i.e. stroke) by reducing local tissue hypoxia and, therefore, the subsequent infarct volume. Native, or pre-existing, collateral density varies widely between individual humans and mice, and very little is known regarding when they form and how they remain stable into adulthood. Thus, we sought to identify factors dictating collateral formation and stabilization. This laboratory previously used genetically altered mouse models to show that collaterals first form in late embryogenesis in a VEGF-Notch pathway-dependent manner. We found that knockdown of pathway member proteins ADAM10 and ADAM17, but not FLT1 (VEGFR1), altered pial collateral formation. Although embryonic VEGF overexpression increased collateral density in embryonic and adult CD1-background mice, it was not sufficient to increase collaterogenesis in the severely collateral-deficient BALB/c strain. Lastly, we showed that constitutive and ubiquitous CLIC4 knockout does not affect embryonic collaterogenesis but caused collaterals to prune shortly after birth. This work both shapes our understanding of collateral formation and stability and identifies targets for potential therapies designed to enhance collateral density in deficient individuals.