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dc.contributor.authorSultan, Ibrahim
dc.contributor.authorRamste, Markus
dc.contributor.authorPeletier, Pim
dc.contributor.authorHemanthakumar, Karthik Amudhala
dc.contributor.authorRamanujam, Deepak
dc.contributor.authorTirronen, Annakaisa
dc.contributor.authorvon Wright, Ylva
dc.contributor.authorAntila, Salli
dc.contributor.authorSaharinen, Pipsa
dc.contributor.authorEklund, Lauri
dc.contributor.authorMervaala, Eero
dc.contributor.authorYlä-Herttuala, Seppo
dc.contributor.authorEngelhardt, Stefan
dc.contributor.authorKivelä, Riikka
dc.contributor.authorAlitalo, Kari
dc.date.accessioned2024-05-15T05:45:26Z
dc.date.available2024-05-15T05:45:26Z
dc.date.issued2024
dc.identifier.citationSultan, I., Ramste, M., Peletier, P., Hemanthakumar, K. A., Ramanujam, D., Tirronen, A., von Wright, Y., Antila, S., Saharinen, P., Eklund, L., Mervaala, E., Ylä-Herttuala, S., Engelhardt, S., Kivelä, R., & Alitalo, K. (2024). Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy. <i>Circulation Research</i>, <i>Ahead of Print</i>. <a href="https://doi.org/10.1161/circresaha.123.324136" target="_blank">https://doi.org/10.1161/circresaha.123.324136</a>
dc.identifier.otherCONVID_213390725
dc.identifier.urihttps://jyx.jyu.fi/handle/123456789/94822
dc.description.abstractBACKGROUND: 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.en
dc.format.mimetypeapplication/pdf
dc.language.isoeng
dc.publisherLippincott Williams & Wilkins
dc.relation.ispartofseriesCirculation Research
dc.rightsIn Copyright
dc.subject.otherangiogenesis
dc.subject.othercoronary vessels
dc.subject.otherheart failure
dc.subject.othermyocardial infarction
dc.subject.otherpregnancy
dc.titleContribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy
dc.typeresearch article
dc.identifier.urnURN:NBN:fi:jyu-202405153593
dc.contributor.laitosLiikuntatieteellinen tiedekuntafi
dc.contributor.laitosFaculty of Sport and Health Sciencesen
dc.type.urihttp://purl.org/eprint/type/JournalArticle
dc.type.coarhttp://purl.org/coar/resource_type/c_2df8fbb1
dc.description.reviewstatuspeerReviewed
dc.relation.issn0009-7330
dc.relation.volumeAhead of Print
dc.type.versionacceptedVersion
dc.rights.copyright© 2024 American Heart Association, Inc.
dc.rights.accesslevelopenAccess
dc.type.publicationarticle
dc.subject.ysosydämen vajaatoiminta
dc.subject.ysoangiogeneesi
dc.subject.ysoraskaus
dc.subject.ysosydäninfarkti
dc.format.contentfulltext
jyx.subject.urihttp://www.yso.fi/onto/yso/p18795
jyx.subject.urihttp://www.yso.fi/onto/yso/p22997
jyx.subject.urihttp://www.yso.fi/onto/yso/p8749
jyx.subject.urihttp://www.yso.fi/onto/yso/p8730
dc.rights.urlhttp://rightsstatements.org/page/InC/1.0/?language=en
dc.relation.doi10.1161/circresaha.123.324136
dc.type.okmA1


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