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

Figures

• 

  Figure 1. Endothelial cell responses to mechanical and inflammatory cues in the valve and vasculature. (A). Schematic of valvular endothelial cell (VEC) responses to their mechanical microenvironment. On the fibrosa surface, oscillatory shear stress induces a pro-inflammatory phenotype characterized by elevated expression of adhesion molecules (ICAM1, VCAM1, and SELE) and increased production of reactive oxygen species (ROS). External oxidative insults and intrinsic ROS-generating pathways further amplify inflammatory signaling, promoting downstream pathways such as TNFα,IL1β,TGFβ,NFκB. These responses shift the VEC–VIC axis toward loss of homeostatic control. In contrast, laminar shear stress on the ventricularis surface enhances protective, anti-calcific, and pro-fibrotic programs that help maintain VIC quiescence and support matrix homeostasis. (B). Vascular endothelial cell responses under disturbed flow. Oscillatory shear stress in arteries similarly upregulates adhesion molecules and is accompanied by heightened SELE expression and enhanced platelet adhesion. This inflammatory state drives metabolic reprogramming, including increased expression of the glycolytic regulator PFKFB3,…

• 

  Figure 2. Lymphatic function in cardiac valves (A). Confocal images of Prox1 (green)-positive lymphatic networks showing VE-cadherin (red)-positive “button-like” and “zipper” junctions in initial and collecting lymphatic vessels, respectively. Adapted from “Buttons in endothelium of initial lymphatics” by Baluk et al., licensed under CC BY-NC-SA 4.0. (B) Cardiac contractions drive lymphatic drainage. RV - Right ventricle, LV - Left Ventricle. Tile scan of transverse view of Prox1-tdTomatoTg/+ mice stained for LYVE1 and Prox1 showing ventricular lymphatics enriched in epicardial surface. Adapted from “Ventricular lymphatics are enriched on the epicardial surface, subepicardial region, and right ventricular septum” by Ware et al., licensed under CC BY-NC 4.0. (C) Prox1-tdT (green) expression on the surface of mitral and aortic valve primarily by VECs and not VICs. Adapted from “Supplemental Figure S13. Prox1-tdTomato expression on the surface of the valves” by Ware et al., licensed under CC BY-NC 4.0. (D) Presence of lymphatic vessels in the mitral valve stained for LYVE1 (magenta), PDPN (yellow), and Prox1-tdT (green). Adapted from “Lymphatic vessels in the left atrium, interatrial septum,…

• 

  Figure 3. Evolutionary emergence of nerve fibers in cardiac valves (A). (i) Frontal view of Drosophila antenna and ampula showing the hemolymph flow (in blue). Reproduced from “Schematic diagram of the Drosophila antenna and frontal pulsatile organ (FPO). (A) Frontal view of antenna and ampulla, showing the flow of hemolymph (blue arrows)” by Alan R. Kay, Daniel F. Eberl, and Jing W. Wang, licensed under CC BY. (ii) Open Drosophila circulatory system wherein a pair of ostia cells facilitates the entry of hemolymph during diastole and is pumped through aorta upon systole. Adapted from “Malformations of cardiac valves in Drosopila. (A) Open circulatory system in the Drosophila larva” by Christian Meyer and Achim Paululat, licensed under CC BY. (B) Role of neuroendocrine signal under hypoxic response in marine bivalve mollusks regulating muscle contraction and dilation of blood vessels in gills. Adapted from “Diagram summarizing available data on the hypoxia stress control and the role of neuroendocrine regulation in the hypoxic response in bivalves. The involvement of CAs, 5-HT, ACh, and NO under hypoxic conditions is shown” by Elena Kotsyuba and Vyacheslav Dyachuk, licensed under CC BY 4.0.…

• 

  Figure 4. Lymphatic and neural characteristics of aortic valve leaflets. Schematic illustrating lymphatic markers and neural filaments in aortic valve leaflets. Valve endothelial cells (VECs) express lymphatic-associated markers: VEGFR-3, LYVE1, PDPN and transcription factors: Foxc2 and Prox1. VECs also release prostaglandins to the cusp tissue, though its valve-specific function remains unclear. Neurotransmitters showed regional specific expression: the aortic root showed presence of acetylcholine- and dopamine-associated fibers, whereas leaflets demonstrate and nitric oxide-associated myelinated nerve fibers. The functions relevance of prostaglandin and nitric oxide in the leaflets is not yet defined.