2024
Cardiovasc Res. 2024 Dec 4;120(15):1884-1897. doi: 10.1093/cvr/cvae202.
Endothelial oestrogen-myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload
Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo, Tokyo 113-8655, Japan. Division of Cardiology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, USA. Department of Computational Diagnostic Radiology and Preventive Medicine, The University of Tokyo Hospital, Tokyo, Japan. Isotope Science Center, The University of Tokyo, Tokyo 113-0032, Japan. Department of Anesthesiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Department of Cardiovascular Medicine, National Center for Global Health and Medicine, Tokyo, Japan. Vascular Medicine Research, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA, USA. Department of Medicine, University of Arizona, Tucson, AZ, USA. Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA.
Service type: Knock-in mice
Abstract
Aims: Oestrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Oestrogen receptor α (ERα) non-nuclear signalling confers protection against heart failure remodelling, involving myocardial cyclic guanosine monophosphate (cGMP)-cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examine the cell type-specific role of ERα non-nuclear signalling in oestrogen-conferred protection against heart failure.
Methods and results: We first assessed the tissue-specific impacts of ERα on the cardiac benefits derived from oestrogen, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3 weeks of pressure overload [transverse aortic constriction (TAC)]. E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signalling in endothelial cells (ECs), employing animals with endothelial-specific inactivation of ERα non-nuclear signalling (ERαKI/KI/Tie2Cre+). Female ovariectomized mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which were associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed by CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+was rescued by myocardial PKG activation from chronic treatment with a soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required a co-existence of intact endothelial ERα signalling in a nitric oxide synthase-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of ECs.
Conclusion: An endothelial oestrogen-myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure overload.
Keywords: Angiogenesis; Cyclic GMP; Heart failure; Mice; Non-nuclear signalling; Oestrogen; Transgenic.
