Smooth Muscle Cell AT1a Receptor in Initiating Events in AAAs

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