The role of adventitial resident Sca‐1+ progenitor cells in angiotensin II‐induced aortic stiffening (867.3)

Abstract

The aortic adventitia contains progenitor cells that express the surface marker stem cell antigen‐1 (Sca‐1). Sca‐1+ cells have been reported to transform into smooth muscle cells and promote neo‐intimal formation. We have previously found a striking deposition of adventitial collagen in mice with experimental hypertension. This fibrotic layer of collagen contributes to aortic stiffening and likely promotes systolic hypertension. Because this collagen deposition occurs at the site of Sca1+ cells, we hypothesized that Sca‐1+ progenitor cells serve as a source of adventitial collagen. Using confocal microscopy we found that chronic angiotensin II infusion causes a dramatic increase of Sca‐1+ cells in the aortic adventitial and peri‐adventitial region. Flow cytometry confirmed that aortic Sca‐1+CD31‐ cells are tripled in angiotensin II‐induced hypertension (5.6±1.6 ×103 vs. 15.9±2.4 ×103 cells/per aorta). These Sca‐1+ cells represent approximately one fourth of total adventitial cells. Angiotensin II infusion induces proliferation of these cells as evidenced by positive ki‐67 staining. We then isolated aortic Sca‐1+ cells in sham and angiotensin II‐treated mice using magnetic‐activated cell sorting and found collagen 1a1 (1.0±0.2 vs. 5.4±0.9), 3a1 (1.0±0.4 vs. 4.7±0.8), 5a1 (1.0±0.4 vs. 3.5±0.8) and fibronectin‐1 (1.0±0.3 vs. 2.7±0.4) genes were significantly upregulated in these cells. These fibrotic genes were also upregulated by 2‐3 fold in CD31+ cells suggesting endothelial to mesenchymal transition. Immunofluorescence staining demonstrated colocalization of Sca‐1 and vimentin, a marker of fibroblasts, indicating that these progenitor cells differentiate into fibroblasts during the onset of hypertension. In conclusion, resident aortic Sca‐1+ progenitor cells likely differentiate into fibroblasts in hypertension and contribute to adventitial collagen deposition and promote angiotensin II‐induced aortic stiffening.Grant Funding Source: Supported by NIH R01 grant HL105294