Classically, basic cardiovascular research has been delimited to investigating one of the two architectural territories of the heart; the myocardium and the coronary vasculature. Technological advances continue to foster mechanistic insights on homeostatic physiology and pathophysiology of the heart. In parallel, translational efforts in gene therapy1 and stem cell biology2 have exploited newly-gained concepts toward creating disease-modifying activities in animal models and clinical trials. Together, these advances have blurred the structural boundaries between the myocardium and the circulation, and brought us to appreciate the key signaling pathways that are common to various domains of the heart as well as the fluidity of molecular signals that play opposing roles depending on the spatial and temporal context.