Integrating Endothelial-Derived Hyperpolarizing Signaling into a Multitarget Therapeutic Strategy for Microvascular Disease

Abstract: Endothelial cells release various vasorelaxing molecules, such as nitric oxide and prostacyclin, along with defined factors that induce hyperpolarization of vascular smooth muscle cells through the opening of calcium-sensitive potassium channels. Potassium channel-dependent vasorelaxation is prevalent in microvessels and can partially compensate for deficiencies in other vasodilatory mechanisms. Enhancing this backup vasorelaxant mechanism may aid the treatment of microvascular disorders, such as cerebral small vessel disease and preeclampsia, a pregnancy-specific hypertensive syndrome, which is characterized by systemic endothelial dysfunction. The development of pharmacological potassium channel openers has encountered significant challenges, including issues of specificity, safety concerns, and off-target effects. This study critically evaluates the advantages and drawbacks of integrating hyperpolarization into a holistic vasorelaxant strategy for managing ischemic disease through single or combination drug therapies.