LAUSR

Cardiac growth is a major adaptive response to elevated workload on the heart, one that facilitates a decrease in ventricular wall stress and helps sustain pump function.1 Because most mammalian cardiomyocytes become terminally differentiated and lose their proliferative ability shortly after birth, cardiac growth in response to various stimuli occurs primarily through cardiomyocyte hypertrophy.1 Cardiac hypertrophy is classified into 2 types, physiological and pathological, which differ from each other in terms of morphological and functional characteristics.2 Physiological hypertrophy, which arises after postnatal growth, pregnancy, and repetitive exercise, develops with preserved normal cardiac function and is reversible after stimulus removal.2 Conversely, pathological hypertrophy is induced by sustained disease-related stress to the heart such as hypertension, valvular diseases, myocardial infarction, or excessive neurohormonal activation.2 The pathological hypertrophy is associated with contractile/diastolic dysfunction and interstitial fibrosis leading to irreversible cardiac remodeling and heart failure.3 Elucidating the factors that determine the difference between physiological and pathological cardiac hypertrophy could offer insights into novel therapeutic strategies for the treatment of heart failure. Hypertrophic growth of the myocardium requires proportional growth of the coronary vasculature to provide adequate oxygen and nutrients to sustain the increased heart mass.2 The development of physiological hypertrophy is accompanied by a corresponding coronary angiogenesis response through upregulation of cardiomyocyte-derived angiogenic factors. The early phase of pressure overload induces coronary angiogenesis through hypoxia-inducible factor-1–dependent upregulation of vascular endothelial growth factor (VEGF) in cardiomyocytes.4 In addition, short-term Akt activation in cardiomyocytes induces physiological hypertrophy with appropriately increased capillary density.5 In turn, pathological hypertrophy involves a mismatch between the number of capillaries and the blood flow demand for hypertrophied cardiomyocytes, resulting in cardiac dysfunction and failure.6 Sustained pressure overload induces an accumulation of p53, which inhibits hypoxia-inducible factor-1 activity, which attenuates the production of angiogenic factors in the myocardium.4 Furthermore, long-term Akt activation results in pathological hypertrophy in which angiogenic factors are downregulated.5 Vascular endothelium is accepted to be an endocrine organ that produces various factors called angiocrines.7–9 The endothelium in the heart secretes nitric oxide, endothelin-1, neuregulin-1, and apelin in the settings of physiological and pathological stimuli and contributes to cardiovascular homeostasis.7,8 Remarkably, a study has recently reported that angiogenic stimulation by placental growth factor overexpression in the heart promotes cardiomyocyte hypertrophy through an nitric oxide–de© 2019 American Heart Association, Inc.