Single-Short Partial Reprogramming of the Endothelial Cells Decreases Blood Pressure via Attenuation of EndMT in Hypertensive Mice

作者：Laena Pernomian, Emily Waigi, Vi Nguyen, Ahmed Dawood Mohammed, Tiago J. Costa, Milene Tavares Fontes, Jason L. Kubinak, Andrew Vieira Aitken, Vinicia C. Biancardi, Kamryn Gleason, Tarek Shazly, David Sinclair, Cameron G. McCarthy, Yunguan Wang, Wenbin Tan, Camilla F. Wenceslau · 发表于：Circulation Research · 年份：2025 · DOI：10.1161/circresaha.124.324909 · 被引用次数：13 · 研究领域：Congenital heart defects research、Angiogenesis and VEGF in Cancer、Nitric Oxide and Endothelin Effects

BACKGROUND: Small artery remodeling and endothelial dysfunction are hallmarks of hypertension. Evidence supports a likely causal association between cardiovascular diseases and endothelial-to-mesenchymal transition (EndMT), a cellular transdifferentiation process in which endothelial cells (ECs) partially lose their identity and acquire mesenchymal phenotypes. EC reprogramming represents an innovative strategy in regenerative medicine to prevent deleterious effects induced by cardiovascular diseases. METHODS: Using partial reprogramming of ECs, via overexpression of Oct-3/4-Sox-2-Klf-4 (OSK) transcription factors, we aimed to bring ECs back to a youthful phenotype in hypertension. Primary ECs were infected with lentiviral vectors (LVs) containing the specific EC promoter Cdh5 (cadherin-5) and the reporter EGFP (enhanced green fluorescent protein) with empty vector (LV control) or LV with Oct-3/4-Sox-2-Klf-4. Confocal microscopy and Western blotting analysis were used to confirm OSK overexpression. Cellular migration, senescence, and apoptosis were evaluated. Human aortic ECs from normotensive patients and patients with hypertension were analyzed after OSK treatments for eNOS (endothelial nitric oxide synthase), nitric oxide (NO), and genetic profile. Male and female normotensive (BPN/3J or blood pressure normal mouse strain) and hypertensive (BPH/2J or blood pressure high mouse strain) mice were treated with LV control or LV with Oct-3/4-Sox-2-Klf-4 and evaluated 10 days post...