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

Autor:	Sultan I; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Ramste M; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Peletier P; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Hemanthakumar KA; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Ramanujam D; Institute of Pharmacology and Toxicology, Technical University of Munich, DZHK partner site Munich Heart Alliance, Germany (D.R., S.E.).; RNATICS GmbH, Planegg, Germany (D.R.)., Tirronen A; A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (A.T., S.Y.-H.)., von Wright Y; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Antila S; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Saharinen P; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland., Eklund L; Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Finland (L.E.)., Mervaala E; Department of Pharmacology (E.M.), Faculty of Medicine, University of Helsinki, Finland., Ylä-Herttuala S; A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland (A.T., S.Y.-H.)., Engelhardt S; Institute of Pharmacology and Toxicology, Technical University of Munich, DZHK partner site Munich Heart Alliance, Germany (D.R., S.E.)., Kivelä R; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Stem Cells and Metabolism Research Program (R.K.), Faculty of Medicine, University of Helsinki, Finland.; Faculty of Sport and Health Sciences, University of Jyväskylä, Finland (R.K.)., Alitalo K; Wihuri Research Institute (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., R.K., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.; Translational Cancer Medicine Program (I.S., M.R., P.P., K.A.H., Y.v.W., S.A., P.S., K.A.), Faculty of Medicine, Biomedicum Helsinki, University of Helsinki, Finland.
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 May 24; Vol. 134 (11), pp. 1465-1482. Date of Electronic Publication: 2024 Apr 24.
DOI:	10.1161/CIRCRESAHA.123.324136
Abstrakt:	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. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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