Minoxidil and Nebivolol Restore Aortic Elastic Fiber Homeostasis in Diabetic Mice via Potassium Channel Activation

Auberi Henry¹Laetitia Vanalderwiert¹Floriane Oszust¹Amandine Wahart¹Daniel A Carvajal Berrio²Eva Brauchle²Katja Schenke-Layland²Juergen Brinckmann³Heiko Steenbock³Laurent Debelle¹Isabelle Six⁴Gilles Faury⁵Stéphane Jaisson^1,6Philippe Gillery^1,6Vincent Durlarch^1,6HERVE SARTELET¹Pascal MAURICE¹Amar Bennasroune¹Laurent MARTINY¹Laurent DUCA¹Beatrice Romier-Crouzet¹Sebastien Blaise^1*

• ¹Université de Reims Champagne-Ardenne, Reims, France
• ²Eberhard Karls Universitat Tubingen, Tübingen, Germany
• ³Universitat zu Lubeck, Lübeck, Germany
• ⁴Universite de Picardie Jules Verne, Amiens, France
• ⁵Universite Grenoble Alpes, Saint-Martin-d'Hères, France
• ⁶Centre Hospitalier Universitaire de Reims, Reims, France

Background: Diabetic patients experience a significant reduction in life expectancy, primarily due to early cardiovascular complications. A key feature is the premature degradation of elastic fibers (EFs), contributing to vascular stiffness. Objective: This study evaluates the capacity of two antihypertensive agents, minoxidil (a KATP channel opener) and nebivolol (a β-blocker with KATP activity), to restore EF homeostasis and arterial elasticity in diabetic mice. Methods: Mice are treated with two antihypertensive agents: minoxidil (an ATP-sensitive potassium (KATP) channel opener) or nebivolol (a β-blocker also active on KATP channels). The degree of wear and functionality of EF are assessed after these treatments. We complement this analysis by identifying molecular actors from smooth muscle cell cultures. Results: Our data show that by applying these antihypertensive agents in cultured vascular smooth muscle cells in vitro and in diabetic mice, we efficiently stimulate elastogenesis and inhibit elastolysis. Therefore, treatments restore functional EFs and limit their degradation. This brings blood pressure values of diseased mice close to normal ones (as in unaffected mice). Elastogenesis pathway stimulation and elastolysis inhibition are induced by the opening of sensitive KATP channels and the regulation of the forkhead box transcription factor (FOXO1). Conclusion: Minoxidil and nebivolol restore EF integrity and limit vascular aging in diabetic mice via K+ channel opening and FOXO1 repression. These findings highlight potassium channel–FOXO1 signaling as a therapeutic axis to counteract diabetic vascular complications.