Akt), and p70 s6 kinase phosphorylation, which lead to the proliferation of endothelial cells and the formation of new blood vessels. Genetic knockout of the apelin gene is associated with a delay in the development of the retinal vasculature. Cardiac The apelin receptor is expressed early during the embryonic development of the heart, where it regulates the migration of cell progenitors fated to differentiate into cardiomyocytes, the contractile cells of the heart. Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility. Aged apelin knockout mice develop progressive impairment of cardiac contractility. Apelin acts as a mediator of the cardiovascular control, including for blood pressure and blood flow. It is one of the most potent stimulators of cardiac contractility yet identified, and plays a role in cardiac tissue remodeling. Apelin levels are increased in left ventricles of patients with chronic heart failure and also in patients with chronic liver disease. Exercise The plasma concentration of apelin is shown to increase during exercise. Paradoxically, exogenous apelin in healthy volunteers reduced VO2 peak (peak oxygen consumption) in an endurance test. Brain Apelin receptor is also expressed in the neurons of brain areas involved in regulating water and food intake. Apelin injection increases water intake and apelin decreases the hypothalamic secretion of the antidiuretic hormone vasopressin. This diuretic effect of apelin in association with its hypotensive effect participates in the homeostatic regulation of body fluid. Apelin is also detected in brain areas which control appetite, but its effects on food intake are very contradictory. Adipose tissue Apelin is expressed and secreted by adipocytes, and its production is increased during adipocyte differentiation and is stimulated by insulin. Most obese people have elevated levels of insulin, which may therefore be the reason why obese people have been reported to also have elevated levels of apelin. Digestive Apelin receptor is expressed in several cell types of the gastro-intestinal tract : stomach enterochromaffine-like cells; unknown cells of endocrine pancreas, colon epithelial cells. In stomach, activation of receptors on enterochromaffine-like cells by apelin secreted by parietal cells can inhibit histamine release by enterochromaffine-like cells, which in turn decreases acid secretion by parietal cells. In pancreas, apelin inhibits the insulin secretion induced by glucose. This inhibition reveals the functional interdependency between apelin signalling and insulin signalling observed at the adipocyte level where insulin stimulate apelin