Myocardial hypertrophy is an adaptation to increased hemodynamic demands. An increase in heart tissue must be matched by a corresponding expansion of the coronary vasculature to maintain and adequate supply of oxygen and nutrients for the heart. The physiological mechanisms that underlie the coordination of angiogenesis and cardiomyocyte growth are unknown. We report that induction of myocardial angiogenesis promotes cardiomyocyte growth and cardiac hypertrophy through a novel NO-dependent mechanism. We used transgenic, conditional overexpression of placental growth factor (PlGF) in murine cardiac tissues to stimulate myocardial angiogenesis and increase endothelial-derived NO release. NO production, in turn, induced myocardial hypertrophy by promoting proteasomal degradation of regulator of G protein signaling type 4 (RGS4), thus relieving the repression of the Gβγ/PI3Kγ/AKT/mTORC1 pathway that stimulates cardiomyocyte growth. This hypertrophic response was prevented by concomitant transgenic expression of RGS4 in cardiomyocytes. NOS inhibitor L-NAME also significantly attenuated RGS4 degradation, and reduced activation of AKT/mTORC1 signaling and induction of myocardial hypertrophy in PlGF transgenic mice, while conditional cardiac-specific PlGF expression in eNOS knockout mice did not induce myocardial hypertrophy. These findings describe a novel NO/RGS4/Gβγ/PI3Kγ/AKT mechanism that couples cardiac vessel growth with myocyte growth and heart size. IntroductionRecent studies have increased appreciation for the relationship between cardiomyocyte growth and angiogenesis and its contribution to molecular regulation of the myocardial hypertrophic response. Myocardial hypertrophy, secondary to increased hemodynamic demands, requires commensurate growth of the coronary vasculature to provide adequate oxygen and nutrients to the increasing cardiac mass; lack of coordination between the myocyte-driven hypertrophic response and the production of angiogenic growth factors hallmarks the transition to heart failure (1). Although vascular endothelium controls a plethora of biological events contributing to cardiovascular homeostasis, including regulation of vascular tone, thrombosis, and myocardial stiffness, little is known about the effect of endothelial signaling on cardiomyocyte growth, regulation of myocardial hypertrophy, and heart size. Our previous observation that a NOS inhibitor, N G -nitro-l-arginine methyl ester (L-NAME), partially prevented angiogenesis-driven myocardial hypertrophy (2) suggests that endothelium-dependent NO production might be responsible for the hypertrophic effect on cardiomyocytes and the increase in heart size.Because there are no known mechanisms that link NO to stimulation of cardiomyocyte hypertrophy, we designed the present study to fill this gap. In cardiomyocytes, G protein-mediated hypertrophic signaling is negatively modulated by regulators of G protein signaling (RGS proteins). Among more than 20 RGS proteins, RGS subtype 4, a GTPase-activating protein for heterotrimeric Gq and ...

Background Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation and network size. Factors regulating these processes have not been determined. Methods and Results We used a dominant-negative IκBαSR construct under control of an endothelial-specific inducible promoter to selectively suppress endothelial NFκB activation during development or in the adult vasculature or in vitro. Inhibition of NFκB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecules expression leading to decreased monocyte influx, reduced HIF-1α levels and a marked decrease in Dll4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching, as treatment with Jagged-1 peptide reduced the size of arterial network to baseline levels. Conclusions These findings identify NFκB as a key regulator of adult and developmental arteriogenesis and collateral formation. NFkB achieves this by regulating HIF1α-dependent expression of VEGF-A and PDGF-BB that are necessary for development and maturation of the arterial collateral network and by regulating Dll4 expression that in turn determines the network’s size and complexity.