As outlined, this axis is stimulated by hypoxia and ischemia, as well as stretch in the heart, i.e., afterload increases, such as hypertension, both of which are risk factors for cardiotoxicity with VSP inhibitor therapy.122 The significance of this pathway has been delineated in conditional knockout mice in which VEGF expression is reduced in a cardiac-specific manner. This evidence concerns the gene VEGFA and hypertensive disorder.