EDN1 and Hyperinsulinemia: Concurrent hyperinsulinemia drives vascular dysfunction by altering vascular smooth muscle reactivity to increase peripheral resistance (34), and activating the renin-angiotensin-aldosterone system (RAAS) via endothelial angiotensin-converting enzyme (ACE)/angiotensin II (ANGII)/angiotensin receptor (AT1R) axis overstimulation while enhancing sympathetic nervous system (SNS) tone (35), collectively elevating MAP through hemodynamic alterations (36, 37); this is compounded by IR-induced endothelial dysfunction disrupting the nitric oxide/endothelin-1 balance (38, 39).