Abstract 4140451: Loss of Stem Cell Antigen-1 Worsens Aortic Remodeling in Angiotensin II-Induced Hypertension

Background: Stem cell antigen-1 (Sca-1) marks progenitor cells that contribute to vessel remodeling by differentiating into vascular smooth muscle cells and related myofibroblasts. We previously demonstrated that Sca-1 is required for pro-fibrotic differentiation following arterial injury. Here, in a mouse model of experimental hypertension (HTN), we assessed the requirement for Sca-1 in aortic dysfunction and remodeling. Methods&Results: Male and female mice homozygous for GFP knock-in/Sca-1 knockout (Sca1KI -/- ), heterozygous littermates (Sca1KI +/- ), and control GFP-labeled Sca-1 reporter mice (Sca1GFP), age 12-14-wk, were subjected to angiotensin II-induced HTN (Ang-II 1000 ng/kg/min) by osmotic mini-pump for 28d, or vehicle (0.9% saline). GFP + CD31 - CD45 - cells from Sca1KI -/- , Sca1KI +/-, and Sca1GFP represent progenitor cells with no-, partial-, or normal Sca-1 expression, respectively. Partial- or total loss of Sca-1 expression exacerbated aortic GFP + CD31 - CD45 - cell expansion, compared to Sca1GFP [Sca1KI -/- 32±7-fold change of vehicle vs. Sca1KI +/- 39±9 vs. Sca1GFP 5±1; n=11-13/group; p<0.0001], suggesting disinhibited progenitor responses. Interestingly, Sca1KI -/- mice manifest blunted HTN in response to Ang-II [Sca1KI -/- 130±9 mmHg vs. Sca1KI +/- 159±8 vs. Sca1GFP 160±10; n=6-7/group; p<0.01]. Partial- or total loss of Sca-1 worsened aortic dilation [Sca1KI -/- 1.25±0.06 mm vs. Sca1KI +/- 1.21±0.06 vs. Sca1GFP 1.04±0.05; n=6-7/group; p<0.05], aortic wall thickness [Sca1KI -/- 105±9 μm vs. Sca1KI +/- 136±16 vs. Sca1GFP 82±5; n=6-7/group; p<0.01], adventitial area [Sca1KI -/- 79±13 mm 2 vs. Sca1KI +/- 178±46 vs. Sca1GFP 51±6; n=6-7/group; p<0.01], and aortic aneurysm formation [Sca1KI -/- 6/17 vs. Sca1KI +/- 6/20 vs. Sca1GFP 2/18]. Underlying these differences, in cultured progenitor cells subjected to TGFβ, pro-fibrotic CD44 expression increased 3.4-fold in Sca-1 deficient progenitors vs . wild-type [54±9% vs. 16±2; n=2-3/group]. Concomitantly, stem cell marker PDGFRα expression on these cultured progenitors was reduced [0.4±0.1% vs. 11±1; n=2-3/group], suggesting depletion of progenitors skewed towards a pro-fibrotic lineage. Conclusion: Partial or complete loss of Sca-1 worsens aortic remodeling in Ang-II HTN by increasing progenitor expansion and pro-fibrotic contributions. These data highlight a critical role for vascular Sca-1 expression, which may inform a novel approach to preventing and treating HTN and associated vascular remodeling.