FELLOWSHIP for Poduri: Role of fibroblast cell-specific AT1aR activation in AngII-induced aortic medial hyperplasia in ascending aorta.

Infusion of angiotensin II (AngII) stimulates diverse effects on smooth muscle cells (SMCs) via angiotensin II type 1a receptor (AT1aR). Previously, we demonstrated that AngII promotes aortic medial thickening through region-specific mechanism through AT1aR. In my previous proposal, we determined the cell-type dependent mechanism in this pathology. Unexpectedly, we found that lack of effects of endothelial or SMCs in AngII-induced medial hypertrophy and hyperplasia. Interestingly, in the interim, using a systemic approach by neural cell-specific (Eno2) AT1aR deficient mice, we found attenuation of AngII-induced medial hypertrophy and hyperplasia restricted to ascending aorta. My preliminary studies show that Eno2 expression is restricted to adventitial aortic fibroblasts in ascending aorta. The role of fibroblasts in AngII-induced aortic hypertrophy is not clear. Potential mechanism include effects of AngII acting on adventitial fibroblasts to influence SMC function. Previous studies have shown that adventitial fibroblast migrate into medial layer in response to injury. However, in response to AngII, migration of adventitial fibroblasts into medial layer has not been determined. I request a third year of support to determine whether this interesting effect is due to neural or fibroblast cell dependent mechanism. With the availability of recently generated fibroblast cell-specific AT1aR deficient mice by the Sponsor’s laboratory would enable us to understand this mechanism. The contribution of fibroblast cell specific in AngII-induced medial hypertrophy and hyperplasia has not been determined. Understanding the role of fibroblast cell in vascular remodeling may identify a basis to develop a target that reduces the onset of progression of many vascular diseases. Based on my preliminary studies and above background information, the proposal tests the hypothesis that AngII promotes medial hyperplasia in via fibroblast dependent mechanism through migration of adventitial fibroblasts into SMC medial layer in ascending aorta. To test this hypothesis I propose the following aims: Aim 1: Determine the role of adventitial fibroblast migration into media in AngII-induced aortic hyperplasia. Aim 2: Determine the role of fibroblast cell-specific AT1aR deficiency in AngII-induced medial hyperplasia.