Cardiomyocyte crosstalk with endothelium modulates cardiac structure, function, and ischemia-reperfusion injury susceptibility through erythropoietin

Jade P Marrow; Razan Alshamali; Brittany A Edgett; Melissa A Allwood; Kyla L S Cochrane; Sara Al-Sabbag; Anmar Ayoub; Kjetil Ask; Gregory M T Hare; Keith R Brunt; Jeremy A Simpson

doi:10.3389/fphys.2024.1397049

Cardiomyocyte crosstalk with endothelium modulates cardiac structure, function, and ischemia-reperfusion injury susceptibility through erythropoietin

Front Physiol. 2024 Jul 1:15:1397049. doi: 10.3389/fphys.2024.1397049. eCollection 2024.

Authors

Jade P Marrow^#^{1

2}, Razan Alshamali^#^{1

2}, Brittany A Edgett^{1

2

3}, Melissa A Allwood^{1

2}, Kyla L S Cochrane^{1

2}, Sara Al-Sabbag¹, Anmar Ayoub⁴, Kjetil Ask⁴, Gregory M T Hare^{2

5

6

7}, Keith R Brunt^{2

8}, Jeremy A Simpson^{1

2}

Affiliations

¹ Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada.
² IMPART Investigator Team Canada, Guelph, ON, Canada.
³ Faculty of Kinesiology, University of Calgary, Calgary, AB, Canada.
⁴ Firestone Institute for Respiratory Health, McMaster University, Hamilton, ON, Canada.
⁵ Department of Anesthesiology and Pain Medicine, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
⁶ Department of Physiology, University of Toronto, Toronto, ON, Canada.
⁷ Keenan Research Centre for Biomedical Science in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.
⁸ Department of Pharmacology, Dalhousie Medicine New Brunswick, Saint John, NB, Canada.

^# Contributed equally.

Abstract

Erythropoietin (EPO) exerts non-canonical roles beyond erythropoiesis that are developmentally, structurally, and physiologically relevant for the heart as a paracrine factor. The role for paracrine EPO signalling and cellular crosstalk in the adult is uncertain. Here, we provided novel evidence showing cardiomyocyte restricted loss of function in Epo in adult mice induced hyper-compensatory increases in Epo expression by adjacent cardiac endothelial cells via HIF-2α independent mechanisms. These hearts showed concentric cellular hypertrophy, elevated contractility and relaxation, and greater resistance to ischemia-reperfusion injury. Voluntary exercise capacity compared to control hearts was improved independent of any changes to whole-body metabolism or blood O₂ content or delivery (i.e., hematocrit). Our findings suggest cardiac EPO had a localized effect within the normoxic heart, which was regulated by cell-specific EPO-reciprocity between cardiomyocytes and endothelium. Within the heart, hyper-compensated endothelial Epo expression was accompanied by elevated Vegfr1 and Vegfb RNA, that upon pharmacological pan-inhibition of VEGF-VEGFR signaling, resulted in a paradoxical upregulation in whole-heart Epo. Thus, we provide the first evidence that a novel EPO-EPOR/VEGF-VEGFR axis exists to carefully mediate cardiac homeostasis via cardiomyocyte-endothelial EPO crosstalk.

Keywords: Cre-Lox; EPAS1 gene; compensation; erythropoiesis; erythropoietin; hemodynamics; vascular endothelial growth factor.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Canadian Institutes of Health Research (CIHR) grants (JAS and KB); National Sciences Engineering Research Council (NSERC) grants (JAS and KB); with NSERC Alexander Graham Bell Canada Graduate Scholarship—Doctoral (JM); Killam Foundation Post-Doctoral Fellowship (BE); Ontario Graduate Scholarships (RA). We acknowledge the philanthropic support for cardiovascular research from David Southen and Betty and Jack Southen of London, ON, Canada, to the laboratory of JAS. The funding sources had no influence on study design, sample collection, data analysis and interpretation, or preparation of this manuscript.