Increased myocardial stiffness activates cardiac microvascular endothelial cell via VEGF paracrine signaling in cardiac hypertrophy.

When the heart is subjected to an increased workload, mechanical stretch together with neurohumoral stimuli activate the "fetal gene program" and induce cardiac hypertrophy to optimize output. Due to a lack of effective methods/models to quantify and modulate cardiac mechanical properties, the connection between these properties and the development of cardiac hypertrophy remains largely unexplored. Here, we utilized an atomic force microscope (AFM) to directly measure the elastic modulus of the hypertrophic myocardium induced by pressure overload. Additionally, we investigated the effects of extracellular elasticity on angiogenesis, which provides blood and nutrition to support cardiomyocyte hypertrophic growth in this process. In response to pressure overload, the myocardium rapidly developed hypertrophy and correspondingly demonstrated a high elastic modulus property. This mechanical feature correlated with enhanced angiogenesis. Mechanistically, we found that a high elastic modulus promoted cultured cardiomyocytes to synthesize and paracrine vascular endothelial growth factor (VEGF) to activate cardiac microvascular endothelial cells. Further analysis showed that the increased elastic modulus enhanced the interaction between Talin1 and integrin β1 to activate the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/hypoxia-inducible factor 1α (Hif-1α) pathway, which contributed to VEGF production. Thus, our study revealed a critical role of the elastic modulus in regulating angiogenesis during the development of cardiac hypertrophy.