Shared circuitry: developmental signaling cascades regulate both embryonic and adult coronary vasculature

Abstract

Ischemic heart disease is the most common cause of heart failure and is among the leading causes of mortality worldwide. Therapies used for the treatment of this disease aim to restore blood flow to severely narrowed or occluded coronary arteries by either catheter-based or surgical means. Although these strategies prove efficacious for many patients, a substantial number of individuals fail to improve following these procedures. Recently, a noninvasive strategy has been proposed, focusing on the use of endogenous growth factors that trigger the growth of new coronary arteries. Using the developing heart as a model, several groups have identified some of the key pathways that not only govern the development of the coronary vascular system but also promote the growth of the adult coronary vasculature. Here, we review the major morphological events and signaling cascades that mediate the formation of the coronary vasculature in the embryo. We further describe the mechanism by which many of these same pathways also regulate the adult coronary vasculature and their potential use in the treatment of ischemic heart disease.

Figure 1

Development of the coronary vascular plexus. A. Whole mount immunostaining with an antibody to Platelet/endothelial cell adhesion molecule-1 (PECAM) showing vascular plexus formation from E11.5 to E13.5 and plexus remodeling at E16.5 in the developing mouse heart. B. Diagram showing morphologic events during coronary vascular development in the mouse. By E11.5, the embryonic heart is encased by the epicardium. Between E12.5 and E13.5, a subset of epicardial cells undergo an epithelial to mesenchymal transformation (EMT) and populate the subepicardial space along with subepicardial blood vessels (subepicardial mesenchyme (SEM)), or migrate into the myocardium and encase intramyocardial blood vessels as perivascular cells. C. Histology of E11.5 and E12.5 illustrating the formation of the subepicardial mesenchyme (marked by green arrowheads). D. PECAM immunostaining at E13.5 showing the relative locations of the subepicardial (arrowhead) and intramyocardial (arrow) blood vessels. E. 3D reconstruction of immunofluorescence images obtained from E13.5 hearts stained with anti-PECAM antibodies showing subepicardial (arrowhead), intramyocardial (arrow) and interconnecting vessels (red arrow) that resemble mature arterial/venous vascular networks. (Adapted from Lavine et al.102).

Figure 2

Major components of FGF and HH signaling pathways. A. The FGF receptor is a single transmembrane domain molecule with an extracellular ligand binding domain (containing three immunoglobulin-like domains, I, II, III) and an intracellular tyrosine kinase domain (TK). FGF ligands interact with immunoglobulin domains I and II. Immunoglobulin domain III is alternatively spliced to encode b and c forms that bind mesenchymal and epithelial FGF ligands, respectively. Heparan sulfate, in the form of a heparan sulfate proteoglycan, serves as a cofactor for FGF binding and receptor activation. Dimerization of the FGF receptor leads to activation of downstream signaling pathways and regulation of target genes. B. The HH receptor, Ptc1, functions to inhibit the multi transmembrane domain protein, Smo, in the absence of ligand. C. In the presence of HH ligand, the inhibitory action of Ptc1 is repressed allowing Smo to activate downstream signaling pathways that ultimately activate Gli transcription factors. Among the targets of the HH signaling pathway are Ptc1 and Gli1.

Figure 3

Model showing known and hypothetical signaling pathways for midgestation heart development. A. Diagram of a mouse E13.5 heart showing the relationship between the endocardium, myocardium, subepicardial mesenchyme, epicardium and coronary vasculature. B. Expanded diagram of the boxed region in A showing signaling pathways operating between the epicardium, myocardium and vasculature. The epicardium serves as a signaling center in which retinoic acid (RA) and potentially other molecules regulate the expression of FGF9 (and potentially FGF16 and FGF20). FGFs released from the epicardium signal through myocardial expressed FGFR1 and FGFR2 to regulate midgestation myocardial growth and suppress myocardial differentiation. By unknown mechanisms, myocardial FGF signaling can regulate epicardial function and Shh expression/signaling (dashed lines). SHH signals back to the myocardium to regulate expression of vasculogenic factors, including VEGFA, VEGFB and ANG2. SHH also acts on the perivascular cell where it regulates the expression of VEGFC and possibly other angiogenic factors. Both VEGFs and ANG2 are required for normal coronary vascular development. SEM, subepicardial mesenchyme.