Pressure overload (PO)-induced heart failure (HF) is a global health burden with poor outcomes. Cardiomyocyte hypertrophy and capillary rarefaction are two features and drivers of PO-induced HF. Metabolism is altered in hypertrophic cardiomyocytes; however, the metabolites secreted by hypertrophic cardiomyocytes to paracrinally regulate capillary density remain to be identified. PO-induced HF was established by transverse aortic constriction in mice. Metabolite secretion was examined by nontargeted metabolomics and enzyme-linked immunosorbent assays. Gene expression was examined by RNA-sequencing and immunoblotting. Protein-promoter binding was examined by chromatin immunoprecipitation-PCR. Cardiomyocyte hypertrophy and cardiac capillary density were examined by immunostaining for -actinin and CD31, respectively. angiogenesis was indicated by proliferation, migration, tube formation, and angiogenic factor expression of endothelial cells (ECs). EC senescence was determined by SA--gal staining and p16 and p21 expression. There was a negative correlation between cardiomyocyte size and capillary density in PO-induced failing hearts, and hypertrophic cardiomyocytes paracrinally inhibited angiogenesis of ECs. 3-Methyl-2-oxovaleric acid (KMV) was the most upregulated metabolite secreted by hypertrophic cardiomyocytes. Notably, KMV treatment resulted in EC senescence and angiogenesis inhibition and exaggerated PO-induced EC senescence, capillary rarefaction, and cardiac dysfunction of mice . Additionally, KMV increased expression and nuclear accumulation of mesenchyme homeobox 2 (Meox2) in ECs, whereas Meox2 knockdown diminished KMV-induced EC senescence and angiogenesis inhibition. Furthermore, Meox2 directly bound to the promoter of the senescence-related gene in ECs, and this binding was enhanced by KMV. The data suggest that hypertrophic cardiomyocytes secrete elevated levels of KMV, which paracrinally increases nuclear accumulation of Meox2 in ECs, where Meox2 binds to the promoter of and thereby triggers EC senescence and subsequent angiogenesis impairment, ultimately driving capillary rarefaction to promote PO-induced HF. The findings identified KMV as a novel metabolite secreted by hypertrophic cardiomyocytes that triggered EC senescence to drive PO-induced capillary rarefaction and subsequent HF development. Targeting this KMV-mediated cardiomyocyte-to-EC signaling has therapeutic potential in the management of PO-induced HF in patients.