Role of VEGF and tissue hypoxia in patterning of neural and vascular cells recruited to the embryonic heart

Abstract

We hypothesized that oxygen gradients and hypoxia-responsive signaling may play a role in the patterning of neural or vascular cells recruited to the developing heart. Endothelial progenitor and neural cells are recruited to and form branched structures adjacent to the relatively hypoxic outflow tract (OFT) myocardium from stages 27-32 (ED6.5-7.5) of chick development. As determined by whole mount confocal microscopy, the neural and vascular structures were not anatomically associated. Adenoviral delivery of a VEGF trap dramatically affected the remodeling of the vascular plexus into a coronary tree while neuronal branching was normal. Both neuronal and vascular branching was diminished in the hearts of embryos incubated under hyperoxic conditions. Quantitative analysis of the vascular defects using our recently developed VESGEN program demonstrated reduced small vessel branching and increased vessel diameters. We propose that vascular and neural patterning in the developing heart share dependence on tissue oxygen gradients but are not interdependent.

Avian embryonic coronary arterio‐venous patterning involves the contribution of different endothelial and endocardial cell populations

“…Because adult coronary veins drain into the coronary sinus, which is a partial derivative of the embryonic sinus venosus (Steding et al, ), we think these primitive embryonic vessels represent a developmental scaffold for the formation of coronary veins. These LC‐FITC + sinus venosus endocardial sprouts progressively encircle the atrioventricular groove, growing from the dorsal cardiac wall toward the ventral one perhaps instructed by VEGF, a major chemotactic signal guiding coronary vessel growth (Tomanek et al, ; Liu et al, ; Tomanek et al, ).…”

VEGF-C and aortic cardiomyocytes guide coronary artery stem development

“…VEGF receptor signaling is an important regulator of coronary vessel development, but a site-specific role of individual family members has not been delineated for stem development. Cardiomyocytes within the main ventricle produce VEGF-A (33,45), and coronary vascular development is decreased when VEGF-A is inhibited (13,46,47). Specific deletion of this factor from cardiac cells primarily affects the microvasculature (48) and coronary vessels within the myocardium (27).…”

Retinoic acid signaling in vascular development

“…VEGFA is frequent target of regulation by RA, underlying RA’s pro-angiogenic effects on vascular growth in the choroid, cerebral cortex, and lung. Tissue hypoxia and subsequent stabilization of hypoxia inducible factor-1α (HIF1α) is a major stimulant of VEGFA production during embryonic development (Lange et al, 2016; Liu et al, 2009; Stone et al, 1995). RA signaling can stimulate VEGFA expression via transcriptional upregulation of Hif1a (Liang, Guo, & Yang, 2013, 2014; Mishra, Kelly, Rumian, & Siegenthaler, 2018).…”