Active endothelial and neural regulation of valve biology, health, and disease.

Cardiac valves are complex, living, yet passive structures whose function depends on their ability to withstand and respond to dynamic hemodynamic forces through coordinated interactions among specialized cell types and regulatory systems. Traditional models of valve biology emphasize the roles of valve endothelial cells (VECs), valve interstitial cells (VICs), immune populations, and a stratified extracellular matrix in maintaining structural integrity and homeostasis. Recent studies have uncovered underappreciated contributors to valvular physiology, including lymphatic vessels and innervation of nerve fibers that contribute to the interstitial fluid balance, immune cell surveillance, metabolic waste removal, leaflet contractility, and homeostasis. The increasing number of animal studies in the last decades has shed light on the processes of lymphangiogenesis and neural development and their function in cardiac valves. Although developmental and homeostatic functions of these systems are increasingly recognized, their roles in pathological settings such as calcific aortic valve disease (CAVD) remain poorly defined. Disease-associated remodeling may obstruct lymphatic vessels, alter neurofilament organization, and exacerbate inflammatory and fibrotic responses that promote calcification. By integrating these understudied endothelial, lymphatic, and neural components into the broader framework of valve biology, this review highlights critical gaps in current understanding and underscores the potential of these systems as sources of early biomarkers, mechanistic insights, and therapeutic targets for next-generation valve repair and tissue engineering strategies.