Neuregulin 1 regulates pericyte function in heart failure with preserved ejection fraction in a sex-specific manner

L. R. Vanicek (Frankfurt am Main)¹, M. Ruz-Jurado (Frankfurt am Main)², V. Puntmann (Frankfurt am Main)³, F. Escher (Berlin)⁴, E. Nagel (Frankfurt am Main)⁵, D. John (Frankfurt am Main)², J. L. de la Pompa (Madrid)⁶, G. Luxan (Frankfurt am Main)⁷, S. Dimmeler (Frankfurt am Main)^2
1Goethe University Frankfurt Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland; ²Goethe Universität Frankfurt am Main Zentrum für Molekulare Medizin, Institut für Kardiovaskuläre Regeneration Frankfurt am Main, Deutschland; ³Universitätsklinikum Frankfurt Goethe CVI Frankfurt am Main, Deutschland; ⁴Deutsches Herzzentrum der Charite (DHZC) Klinik für Kardiologie, Angiologie und Intensivmedizin | CBF Berlin, Deutschland; ⁵Universitätsklinikum Frankfurt Kardiovaskuläre Bildgebung Frankfurt am Main, Deutschland; ⁶Centro Nacional de Investigaciones Cardiovasculares (CNIC) Madrid, Spanien; ⁷Goethe Universität Frankfurt am Main Institute of Cardiovascular Regeneration Frankfurt am Main, Deutschland

Heart failure with preserved ejection fraction (HFpEF) is characterized by stiffening of the left ventricle and an increase in left ventricular wall thickness, leading to increased end-diastolic pressure and consequent inadequate filling of the left ventricle. There is growing evidence suggesting that microvascular dysfunction is a key factor driving HFpEF. Endothelial cells play an essential role maintaining cardiovascular homeostasis by regulating vascular tone, nutrient supply and immune cell adhesion. However, molecular alterations in endothelial cells during the development of HFpEF are only partially understood.

Here, we show that HFpEF patients show microvascular dysfunction characterized by increased capillary perimeter and a reduction in pericyte coverage. Single nucleus RNA-sequencing of cardiac biopsies from HFpEF patients revealed the upregulation of genes related to transcriptional processes and cell junctions and the downregulation of genes related to translational processes and ribosomal components in endothelial cells. Specifically, Neuregulin 1 (NRG1) is highly upregulated in endothelial cells in HFpEF patients. To study the effects of NRG1 upregulation, we treated cardiac cells in vitro. Our findings indicate that NRG1 influences pericyte function in a sex-specific manner. NRG1 reduces pericyte viability, inhibits pericyte adhesion and reduces the expression of pericyte marker PDGFRB and CSPG4. In contrast, in female pericytes NRG1 enhanced pericyte viability and migration. Finally, endothelial specific overexpression of NRG1 in adult mice mimics some of the features of HFpEF. Specifically, NRG1 reduced pericyte coverage and pericyte intercapillary connections with effects more pronounced in male mice compared to females. Additionally, male mice show increased IL-1β expression suggestive of enhanced inflammation. These findings demonstrate that NRG1 modulates pericyte function in a sex-specific manner contributing to microvascular dysfunction, a hallmark of HFpEF.