Fellowship for Kelly Putnam: Adipocyte Angiotensin Type 1a Receptor Deficiency in Atherosclerosis and Abnormal Aortic Aneurysms

Vascular diseases, such as atherosclerosis and abdominal aortic aneurysms (AAA), are known precursors to heart disease and stroke, which are both in the top three leading causes of death in the U.S. The success of pharmacological renin-angiotensin system (RAS) antagonists in reducing vascular diseases and associated morbidities strongly suggests the RAS is involved in these diseases. Animal studies with genetic deficiencies of key RAS components, including the Angiotensin Type 1a Receptor (AT1aR), confirm that the primary peptide of the RAS, Angiotensin II (AngII), plays a causative role in the development of atherosclerosis and AAAs. While mice with whole body deficiency of the AT1aR show dramatic reductions in these diseases, cell-specific knockouts of the AT1aR in endothelial cells, smooth muscle cells, and leukocytes fail to exhibit any changes in disease incidence. This suggests the receptor in another cell type is responsible for mediating the detrimental effects of AngII. Adipocytes are gaining interest as a potential mediator of vascular disease since adipose tissue surrounds blood vessels with no anatomical barrier to prohibit crosstalk via inflammatory adipocytokines/chemokines. Additionally, AngII is known to promote inflammatory cytokine production in other cell types and preliminary data suggests it does the same in adipocytes. The working hypothesis of this proposal is that AngII acts at adipocyte AT1aR to initiate inflammatory adipocytokine production and promote atherosclerosis and AAA formation. AngII may promote macrophage infiltration into perivascular adipose tissue, priming the vessel such that an insult to endothelial cells (as in atherosclerosis) or smooth muscle cells (as in AAA formation) will result in macrophage migration from adipose into the vessel wall, promoting disease progression. In order to test this hypothesis, we have developed a model of adipocyte-specific AT1aR deficiency using the Cre/Lox system on the LDLR-/- background, which induces hypercholesterolemia and makes mice prone to atherosclerosis upon Western diet (high fat, high cholesterol) feeding. Changes in systemic concentrations and local production of adipocytokines/chemokines, as well as their influence on macrophage migration, will be investigated as potential mechanisms for reductions in disease incidence due to adipocyte-AT1aR deficiency.