Mechanical regulation of cardiac growth and remodeling by VCAN-GPR126 signaling

The heart develops and functions in the presence of mechanical forces generated by its contraction. Mechanical forces are believed to direct cardiac growth, as well as pathologic remodeling of the mature heart in response to mechanical load such as hypertension. However, the mechanotransducing receptors and signaling pathways that mediate such responses remain undefined, at there are presently no therapies for acquired heart diseases that directly target this mechanism. Adhesion G protein-coupled receptors (aGPCRs) are activated by mechanical displacement of their large, ligand-binding N-termini from the transmembrane receptor body. The aGPCR GPR126 is expressed in the endocardium and required for embryonic survival. To identify the endogenous ligand for GPR126 we created a GPR126-Tango allele that reports aGPCR signaling in vivo. Our preliminary studies reveal that endocardial GPR126 signaling in the developing heart corresponds closely with the level of versican (VCAN), a proteoglycan that forms a deformable matrix known as cardiac jelly that separates endocardial and myocardial cells. VCAN expression is re-activated in the mature heart by mechanical strain, and we also observe re-activation of GPR126-Tango signaling following aortic constriction or myocardial infarction. This proposal will test the hypothesis that VCAN-GPR126 signaling is stimulated by mechanical forces during both cardiac development and postnatal remodeling. Aim 1 will use newly conditional and mutant Vcan and Gpr126 mouse alleles generated in our laboratory, as well as traditional biochemical approaches, to test the model that GPR126 is an endothelial cell VCAN receptor that is activated by mechanical displacement of its N-terminus. Aim 2 will test whether GPR126 is required during development of the cardiac conduction system, and fully define the role of GPR126 during pathologic cardiac remodeling in response to pressure overload in the mature heart. The proposed studies are predicted to define a new molecular mechanism by which the heart responds to mechanical force, and a potential target for therapies designed to blunt this response under pathologic conditions.