Endothelial oestrogen-myocardial cyclic guanosine monophosphate axis critically determines angiogenesis and cardiac performance during pressure overload.

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  • Additional Information
    • Source:
      Publisher: Oxford Journals Country of Publication: England NLM ID: 0077427 Publication Model: Print Cited Medium: Internet ISSN: 1755-3245 (Electronic) Linking ISSN: 00086363 NLM ISO Abbreviation: Cardiovasc Res Subsets: MEDLINE
    • Publication Information:
      Publication: 2008- : Oxford : Oxford Journals
      Original Publication: London, British Medical Assn.
    • Subject Terms:
      Estrogen Receptor alpha*/metabolism ; Estrogen Receptor alpha*/genetics ; Estrogen Receptor alpha*/deficiency ; Signal Transduction* ; Myocytes, Cardiac*/metabolism ; Myocytes, Cardiac*/pathology ; Neovascularization, Physiologic* ; Cyclic GMP*/metabolism ; Endothelial Cells*/metabolism ; Estradiol*/pharmacology ; Estradiol*/metabolism ; Disease Models, Animal* ; Heart Failure*/metabolism ; Heart Failure*/physiopathology ; Heart Failure*/genetics ; Heart Failure*/pathology ; Ventricular Function, Left* ; Ovariectomy* ; Ventricular Remodeling*; Animals ; Female ; Mice, Knockout ; Cells, Cultured ; Cyclic GMP-Dependent Protein Kinases/metabolism ; Mice, Inbred C57BL ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor A/genetics ; Soluble Guanylyl Cyclase/metabolism ; Soluble Guanylyl Cyclase/genetics ; Coculture Techniques ; Human Umbilical Vein Endothelial Cells/metabolism ; Angiogenesis
    • 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.
      Competing Interests: Conflict of interest: none declared.
      (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
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    • Grant Information:
      JSPS Overseas Research Fellowship 2022; Takeda Science Foundation; Japan Foundation for Applied Enzymology; AHA Northeast Research Consortium Postdoctoral Fellowship; 23gk0210037h0001 AMED; Japan Heart Foundation; JP18K08096 KAKENHI; R01 DK062729 United States DK NIDDK NIH HHS; DK 062729 United States GF NIH HHS; Uehara Research Fellowship; SENSHIN Medical Research Foundation
    • Contributed Indexing:
      Keywords: Angiogenesis; Cyclic GMP; Heart failure; Mice; Non-nuclear signalling; Oestrogen; Transgenic
    • Accession Number:
      0 (Estrogen Receptor alpha)
      H2D2X058MU (Cyclic GMP)
      4TI98Z838E (Estradiol)
      0 (Esr1 protein, mouse)
      EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
      0 (Vascular Endothelial Growth Factor A)
      EC 4.6.1.2 (Soluble Guanylyl Cyclase)
      0 (vascular endothelial growth factor A, mouse)
    • Publication Date:
      Date Created: 20240911 Date Completed: 20241210 Latest Revision: 20241212
    • Publication Date:
      20241212
    • Accession Number:
      PMC11630045
    • Accession Number:
      10.1093/cvr/cvae202
    • Accession Number:
      39259833