We propose a central hypothesis that Angll initiates AAA formation through smooth muscle cell AT1 receptoractivation regulating the LRP-uPAR axis to promote medial macrophage accumulation. To test thishypothesis, we propose the following specific aims:
Aim >1: Determine the contribution of smooth musclecell-specific AT1a receptors to AAA production and cellular changes in the aorta. The effects of smoothmuscle cell specific AT1a receptor deficiency on AAA development will be determined in Angll-infused LDLreceptor -/- mice. We will use AT1a receptor floxed mice in which smooth muscle cell deficiency will beaccomplished with Cre expressed under the control of SM22. The effect of smooth muscle cell AT1areceptor deficiency will be determined on the cellular changes that occur in the initiating phase of AAAdevelopment.
Aim 2 : Determine the role of Angll on regulation of LRP in smooth muscle cells and the effectof reduced LRP on susceptibility to AAA development. We will determine the mechanisms by which Anglldownregulates LRP. This will be performed in cultured smooth muscle cells derived from specific aorticregions. We will determine if mice that are hypomorphic for LRP are more susceptible to Angll-inducedAAAs. 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 -/- miceto determine its role in development of Angll-induced AAAs. 'Forward' and 'reverse' bone marrowtransplantation 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 marrowtransfer studies with mice expressing allelic variants of CD45 will be used to define whether Angll-inducedaccumulation of macrophages in the aortic layers originate from blood-borne monocytes or residentmacrophages in the adventitia of the aorta.
Showing the most recent 10 out of 43 publications
