biostudies-literatureDeBenedittis PInnovative Medicines InitiativeNational Institute for Health Research University College LondonBritish Heart FoundationDuke UniversityEdna and Fred L. Mandel, Jr. FoundationMedical Research CouncilNHLBI NIH HHSNational Institute for Health Research (NIHR)National Institutes of HealthUK Research and Innovationdev200654https://www.ebi.ac.uk/biostudies/studies/S-EPMC10692274biostudies-literatureUnknown149(18)Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.Development (Cambridge, England)Coupled myovascular expansion directs cardiac growth and regeneration.PMC10692274R01 HL157277MR/S003754/1FS/18/65/34186C116074R03 HL144812DeBenedittis PHenry AKarpurapu ATata PRKarra RMcCord TJBrezitski KKontos CDBaker CELumbers RTPrasad AKobayashi YShah SHThomas MCfalseCoupled myovascular expansion directs cardiac growth and regeneration.Heart regeneration requires multiple cell types to enable cardiomyocyte (CM) proliferation. How these cells interact to create growth niches is unclear. Here, we profile proliferation kinetics of cardiac endothelial cells (CECs) and CMs in the neonatal mouse heart and find that they are spatiotemporally coupled. We show that coupled myovascular expansion during cardiac growth or regeneration is dependent upon VEGF-VEGFR2 signaling, as genetic deletion of Vegfr2 from CECs or inhibition of VEGFA abrogates both CEC and CM proliferation. Repair of cryoinjury displays poor spatial coupling of CEC and CM proliferation. Boosting CEC density after cryoinjury with virus encoding Vegfa enhances regeneration. Using Mendelian randomization, we demonstrate that circulating VEGFA levels are positively linked with human myocardial mass, suggesting that Vegfa can stimulate human cardiac growth. Our work demonstrates the importance of coupled CEC and CM expansion and reveals a myovascular niche that may be therapeutically targeted for heart regeneration.2022-01-01T00:00:00Z2022 Sep2026-05-29T00:47:03.744Z2025-04-05T11:45:55.686ZS-EPMC106922743613469010.1242/dev.200654