Rosuvastatin Reduces Allostatic Overload due to Mechanical Strain: A New Finding on Vascular Remodeling Linked to Hypertension in Spontaneously Hypertensive Rats

INTRODUCTION: Chronic hemodynamic overload due to hypertension produces cardiovas-cular remodeling, where mechanical stretch (MS) deformation, neurohumoral factors, and/or chronic interaction promote a harmful allostatic overload. Previously, our laboratory demonstrated that rosuvastatin modulates the NO-Hsp70-WT1 pathway during MS at the renal level, and other authors have reported that some statins inhibit the proliferation of rat vascular smooth muscle cells (VSMC) induced by MS. Therefore, this study aims to evaluate, in VSMC culture, the possible modulation of rosuvastatin on NO-Hsp70-WT1 signaling linked to MS and its impact on vascular remodeling due to hypertension. METHODS: After 10 weeks of age, mesenteric vascular smooth muscle cells (VSMCs) were cultured from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Prior to cell culture, systolic blood pressure (SBP) was measured: SHR exhibited SBP of 180 ± 10 mmHg, while WKY rats had SBP of 125 ± 8 mmHg. Eight experimental groups were established: SHR and WKY, each with or without mechanical stretch (MS) for 48 hours (Flexcell® system), and with or without treatment with rosuvastatin (10⁻⁵ mol/L). Apoptosis was assessed by flow cytometry, while fibrosis was evaluated via TGF-β levels. Nitric oxide (NO) levels, as well as WT1 and Hsp70 expression, were also analyzed. RESULTS: SHR cultures without MS vs WKY without MS showed higher apoptosis/fibrosis and low NO, WT1, and Hsp70 (p < 0.01). Notably, WKY with MS was similar to SHR without MS. Fur-thermore, when comparing SHR with MS vs SHR without MS, we verified more significant apop-tosis/fibrosis with lower NO, WT1, and Hsp70 (p < 0.01). However, rosuvastatin reduced these differences, promoting the restoration of the altered parameters. DISCUSSION: Mechanical Stretch (MS) induces apoptosis and fibrosis in vascular smooth muscle cells (VSMCs) from hypertensive rats, correlating with impaired nitric oxide (NO) production. Rosuvastatin treatment significantly attenuated MS-induced damage and restored NO bioavaila-bility. Critically, MS downregulated the expression of WT1 and Hsp70, and rosuvastatin restored these levels, suggesting that its protective effects are mediated through the modulation of the NO-Hsp70-WT1 signaling pathway. This study proposes a novel mechanistic framework for statin-mediated vascular protection, highlighting the potential of rosuvastatin to mitigate mechanical stress-induced cardiovascular remodeling in hypertension and related pathologies. CONCLUSION: Rosuvastatin can reduce vascular remodeling and allostatic overload during hyper-tension by decreasing MS-associated apoptosis/fibrosis in mesenteric VSMC and regulating the NO-Hsp70-WT1 axis, which highlights its potential clinical use in treating hypertension-induced vascular remodeling.