Smooth Muscle Cell AT1a Receptor in Initiating Events in AAAs

University Of Kentucky, Lexington KY

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Abstract

We propose a central hypothesis that Angll initiates AAA formation through smooth muscle cell AT1 receptor[unreadable] activation regulating the LRP-uPAR axis to promote medial macrophage accumulation. To test this[unreadable] hypothesis, we propose the following specific aims: Aim>1: Determine the contribution of smooth muscle[unreadable] cell-specific AT1a receptors to AAA production and cellular changes in the aorta. The effects of smooth[unreadable] muscle cell specific AT1a receptor deficiency on AAA development will be determined in Angll-infused LDL[unreadable] receptor -/- mice. We will use AT1a receptor floxed mice in which smooth muscle cell deficiency will be[unreadable] accomplished with Cre expressed under the control of SM22. The effect of smooth muscle cell AT1a[unreadable] receptor deficiency will be determined on the cellular changes that occur in the initiating phase of AAA[unreadable] development. Aim 2: Determine the role of Angll on regulation of LRP in smooth muscle cells and the effect[unreadable] of reduced LRP on susceptibility to AAA development. We will determine the mechanisms by which Angll[unreadable] downregulates LRP. This will be performed in cultured smooth muscle cells derived from specific aortic[unreadable] regions. We will determine if mice that are hypomorphic for LRP are more susceptible to Angll-induced[unreadable] AAAs. This will be performed in mice that are deficient in RAP, the molecular chaperone of LRP. Aim 3:[unreadable] Determine the contribution of uPAR to the development of Angll-induced AAAs. We will use uPAR -/- mice[unreadable] to determine its role in development of Angll-induced AAAs. "Forward" and "reverse" bone marrow[unreadable] transplantation studies will determine the tissue loci of uPAR involved in Angll-induced AAAs. Aim 4:[unreadable] Determine the origin of medial macrophages accumulated in the aorta during Angll-infusion. Bone marrow[unreadable] transfer studies with mice expressing allelic variants of CD45 will be used to define whether Angll-induced[unreadable] accumulation of macrophages in the aortic layers originate from blood-borne monocytes or resident[unreadable] macrophages in the adventitia of the aorta.