Fellowship Zhu: Novel Mechanism of Atherosclerosis: AT1aR in Decorin-Lineage Cells

ABSTRACT The renin-angiotensin system plays a pivotal role in atherogenesis; however, the evolving mechanism responsible for this pathogenic effect remains undefined. Angiotensin II (AngII) type 1 receptor (AT1R in humans; AT1aR in mice) is the primary receptor through which AngII, the major bioactive peptide, exerts its effects on atherosclerosis. My sponsors’ long- term research has demonstrated that AT1aR activation contributes to atherosclerosis; however, AT1aR in myeloid cells, endothelial cells, or smooth muscle cells, did not affect atherosclerosis, as determined in hypercholesterolemic mice with cell-specific deletion of AT1aR. My preliminary studies using single-cell and spatial RNA sequencing revealed that AT1aR expression is predominantly localized to fibroblasts, abundant with decorin (DCN+) in both human and mouse atherosclerosis. In normal aortic wall, DCN+ cells are restricted to the adventitia; however, during atherosclerosis development and progression, DCN+ cells are present not only in the adventitia but also in the media and atherosclerotic plaques, accompanied by increased collagen 1A1 expression and decreased actin alpha 2 expression, indicating phenotypic changes in DCN+ cells. Recently, my sponsors developed Dcn-Cre ERT2 mice, which provided evidence that Dcn-lineage cells are predominantly in the adventitia of normal aortas. Based on my preliminary data and the long-standing work from my sponsors’ lab, I hypothesize that AT1aR activation drives Dcn- lineage cell migration and proliferation, thereby promoting atherosclerosis development and progression. Two aims are proposed to test this hypothesis. Aim 1 will use our unique Dcn- CreERT2; mT/mG mice to track DCN-lineage cell fate and phenotypic changes in hypercholesterolemic mice. I will also culture Dcn-lineage cells to examine their response to oxidized LDL. Aim 2 will determine whether AT1aR in Dcn-lineage cells contributes to atherosclerosis in hypercholesterolemic mice.