Effects of chronically increased VEGF-A on the aging heart.

Whether approaches to chronically increase VEGF-A in the heart may have beneficial effects and prevent the development of heart failure, in part by improving cardiac perfusion, or whether this increase could have detrimental effects on cardiac performance in the aging heart, has not been tested yet. In this study, a genetic mouse model with a chronic increase in VEGF-A in the heart is shown to have increased cardiac angiogenesis and develop cardiac hypertrophy with enhanced basal cardiac performance with age progression. However, in aged hearts, this increase in VEGF-A was associated with higher expression of fetal cardiac genes and reduced cardiac performance after β-agonistic stress, features consistent with pathologic cardiac hypertrophy. Expression of Nod-like receptor protein (NLRP)-3 was increased in the hearts of the mice, and its genetic inactivation prevented increased fetal cardiac gene expression and partially rescued the impaired cardiac performance after β-agonistic stimulation in aged hearts without reducing cardiac angiogenesis or hypertrophy. Thus, although a chronic increase in cardiac VEGF-A may improve cardiac perfusion, long-term upregulation of VEGF-A leads to reduced cardiac performance under stress, an effect that can be partially inhibited by NLRP3 inactivation. Targeting NLRP3 shifts the VEGF-A-induced cardiac hypertrophy from a pathologic toward a more physiologic hypertrophy.-Marneros, A. G. Effects of chronically increased VEGF-A on the aging heart.