Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy

作者：Ibrahim Sultan, Markus Ramste, Pim Peletier, Karthik Amudhala Hemanthakumar, Deepak Ramanujam, Annakaisa Tirronen, Ylva von Wright, Salli Antila, Pipsa Saharinen, Lauri Eklund, Eero Mervaala, Seppo Ylä‐Herttuala, Stefan Engelhardt, Riikka Kivelä, Kari Alitalo · 发表于：Circulation Research · 年份：2024 · DOI：10.1161/circresaha.123.324136 · 被引用次数：20 · 研究领域：Cardiac Fibrosis and Remodeling、Congenital heart defects research、Angiogenesis and VEGF in Cancer

BACKGROUND: Preclinical studies have shown the therapeutic potential of VEGF-B (vascular endothelial growth factor B) in revascularization of the ischemic myocardium, but the associated cardiac hypertrophy and adverse side effects remain a concern. To understand the importance of endothelial proliferation and migration for the beneficial versus adverse effects of VEGF-B in the heart, we explored the cardiac effects of autocrine versus paracrine VEGF-B expression in transgenic and gene-transduced mice. METHODS: We used single-cell RNA sequencing to compare cardiac endothelial gene expression in VEGF-B transgenic mouse models. Lineage tracing was used to identify the origin of a VEGF-B-induced novel endothelial cell population and adeno-associated virus-mediated gene delivery to compare the effects of VEGF-B isoforms. Cardiac function was investigated using echocardiography, magnetic resonance imaging, and micro-computed tomography. RESULTS: Unlike in physiological cardiac hypertrophy driven by a cardiomyocyte-specific VEGF-B transgene (myosin heavy chain alpha-VEGF-B), autocrine VEGF-B expression in cardiac endothelium (aP2 [adipocyte protein 2]-VEGF-B) was associated with septal defects and failure to increase perfused subendocardial capillaries postnatally. Paracrine VEGF-B led to robust proliferation and myocardial migration of a novel cardiac endothelial cell lineage (VEGF-B-induced endothelial cells) of endocardial origin, whereas autocrine VEGF-B increased proliferation ...