The purpose of this project is to improve our understanding of arteriogenesis in ischemia. This process, consisting of outward remodeling of pre-existing arteriole anastomoses and formation of new or """"""""neo-collaterals"""""""", is not well understood. Moreover, many patients with ischemic disease show a deficit in collateral development. A mouse strain with a severe deficiency in recovery of perfusion after artery ligation has been identified, but the reasons for the impairment are unknown.
Aim I will use new methods we have developed for imaging arteriogenesis, will introduce a new strategy for study of neo-collateral formation, and will test the hypothesis that formation of neo-collaterals is defective in the strain. There is evidence that the morphogenic pathway, Sonic hedgehog-notch, which mediates early vascular development, may be reactivated in adults during injury and/or remodeling. A role for this pathway in arteriogenesis has not been studied. Our preliminary data suggest Shh signaling is important in collateral maturation. Therefore, Aim II will examine the hypothesis that Shh-notch signaling contributes to pre-existing collateral maturation and neo-collateral formation, and that it is defective in the impaired strain.
|Chalothorn, Dan; Faber, James E (2010) Strain-dependent variation in collateral circulatory function in mouse hindlimb. Physiol Genomics 42:469-79|
|Chalothorn, Dan; Zhang, Hua; Smith, Jennifer E et al. (2009) Chloride intracellular channel-4 is a determinant of native collateral formation in skeletal muscle and brain. Circ Res 105:89-98|
|Clayton, Jason A; Chalothorn, Dan; Faber, James E (2008) Vascular endothelial growth factor-A specifies formation of native collaterals and regulates collateral growth in ischemia. Circ Res 103:1027-36|
|Lewis, Chandani; Zhu, Weifei; Pavkov, Mircea L et al. (2008) Arginase blockade lessens endothelial dysfunction after thrombosis. J Vasc Surg 48:441-6|
|Chalothorn, Dan; Clayton, Jason A; Zhang, Hua et al. (2007) Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains. Physiol Genomics 30:179-91|