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

Circ Res. 2024 May 24;134(11):1465-1482. doi: 10.1161/CIRCRESAHA.123.324136. Epub 2024 Apr 24.

Abstract

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 of VEGF-B-induced endothelial cells but failed to promote their migration and efficient contribution to myocardial capillaries. The surviving aP2-VEGF-B offspring showed an altered ratio of secreted VEGF-B isoforms and developed massive pathological cardiac hypertrophy with a distinct cardiac vessel pattern. In the normal heart, we found a small VEGF-B-induced endothelial cell population that was only minimally expanded during myocardial infarction but not during physiological cardiac hypertrophy associated with mouse pregnancy.

Conclusions: Paracrine and autocrine secretions of VEGF-B induce expansion of a specific endocardium-derived endothelial cell population with distinct angiogenic markers. However, autocrine VEGF-B signaling fails to promote VEGF-B-induced endothelial cell migration and contribution to myocardial capillaries, predisposing to septal defects and inducing a mismatch between angiogenesis and myocardial growth, which results in pathological cardiac hypertrophy.

Keywords: angiogenesis; coronary vessels; heart failure; myocardial infarction; pregnancy.

MeSH terms

  • Animals
  • Autocrine Communication
  • Cardiomegaly* / genetics
  • Cardiomegaly* / metabolism
  • Cardiomegaly* / pathology
  • Cell Lineage*
  • Cell Movement
  • Cell Proliferation
  • Endocardium* / metabolism
  • Endocardium* / pathology
  • Endothelial Cells* / metabolism
  • Endothelial Cells* / pathology
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic*
  • Paracrine Communication
  • Vascular Endothelial Growth Factor B* / genetics
  • Vascular Endothelial Growth Factor B* / metabolism

Substances

  • Vascular Endothelial Growth Factor B
  • vascular endothelial growth factor B, mouse