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Flow (shear stress)-mediated mechanotransduction in the endothelial cell and flow-mediated remodeling in vivo

Daniel Henrion


daniel.henrion @ inserm.fr

daniel.henrion@univ-angers.fr

 

 

 

 

State of the art and objectives

 

First axis

Resistance arteries are located upstream capillaries control blood delivery to tissues at relevant flow and pressure. Disorders in their structure and function can raise downstream capillary pressure and thus induce organ damage. The endothelium has a key role in the control of local blood flow by resistance arteries. Flow (shear stress) induces the production of vasodilators by endothelial cells leading to flow-mediated dilatation (FMD). Reduced FMD is the hallmark of endothelium dysfunction. FMD is altered early in ageing especially when associated with cardiometabolic risk factors. Women are protected against cardiovascular disorders compared to men.Nevertheless, a unique case of lack of ERα described in a man was associated with early atherosclerosis and a selective loss of FMD. Indeed, estradiol and endothelial estrogen receptor alpha (ERα) are involved in atheroprotection and flow-mediated outward remodeling (FMR, or collateral arteries growth in ischemic diseases).

We also began to decipher the respective roles of classic nuclear, transcriptional ERα and of a more recently characterized extranuclear membrane ERα. Thus, we hypothesize that membrane ERα is an important actor of endothelial mechanotransduction (shear stress signaling).


This project is supported by the National Agency for Research (ANR, Estroshear Project).

 

Second axis

Besides the estrogen receptor, circulating and tissue lipids such as sphingosine-1-phosphate (S1P) are potent regulators of vascular homeostasis. S1P is an abundant plasma lipid that is carried on high-density lipoproteins (HDL) and that mediates in part their vascular protective functions through activation of G protein-coupled receptor signaling. S1P signaling is essential for the integrity of the cardiovascular system. A growing body of evidence suggests that S1P may sustain pressure-induced (myogenic) tone and mediate endothelial shear stress sensing and dilatation in resistance arteries.

Using mouse lines engineered for temporal and spatial deficiency in S1P production and S1P receptors, we will address the potential of blood and vessel wall-derived S1P to modulate vascular function in isolated vessels and organs and in the intact organism. We expect finding how S1P signaling is engaged to regulate resistance artery function and blood pressure, and thus on the potential diagnostic value of blood S1P for microvascular health and the development of hypertension.

This project is supported by the ANR (SphiPerVasc Project).

 

Third axis

Recent studies have shown the presence of estrogen receptors in mitochondria and suggested that estradiol alters mitochondrial function. We have demonstrated that in vivo estrogen replacement at physiological doses leads to increased levels of key mitochondrial proteins, such as cytochrome C, mitochondrial transcription factors and antioxidant enzymes, in cerebral blood vessels of ovariectomized female rats. Estrogens are potent regulator of mitochondria biogenesis and several recent studies suggest a role for the mitochondria in flow-mediated signaling.

Taking advantage of the expertise of team 1 (Mitolab) we investigate the role of mitochondria dynamics in the response to shear stress of endothelial cells.

Mitoshear project supported by the “Fondation pour la Recherche Médicale”.

People involved in the project

Daniel Henrion, Pharm.D., Ph.D., DR1 INSERM
Anne-Laure Guihot, Assistant Engineer CNRS
Emilie Vessières, Engineer, UA
Linda Grimaud, Assistant-Engineer, UA
Coralyne Proux, Engineer, CNRS (Mitoshear project)
Jordan Rivron, Assistant-Engineer, UA and ANR (Estroshear project)
Manuela Garcia, Engineer, UA and ANR (Sphipervasc project)
Ahmad Chehaitly, Ph.D. student, (Mitoshear project)

Project supported by

  • Fondation pour la Recherche Médicale (2018-2020), MitoShear project (coord. Henrion).
  • ANR (2018-2021), Estroshear project (coord. D. Henrion, collab. with JF Arnal, Toulouse)
  • ANR (2020-2022), Sphipervasc project (Coord. E. Camerer, PARCC, Paris)

Collaborations

  • JF Arnal, Dr. F. Lenfant & Dr. C. Fontaine (I2CM, INSERM U1048, Toulouse) ; Estroshear project (ANR).
  • B. Lévy (PARCC, INSERM U970), Risk factors and neurovascular diseases.
  • M. Iglarz (Idorsia Pharmaceutical ltd, Basel, Switzerland). Risk factors and vascular aging.
  • E. Camerer (PARCC, INSERM U970), Sphipervasc project (ANR)
  • P. Bonnin (Service de Physiologie Clinique Explorations Fonctionnelles, INSERM U965, Hôpital Lariboisière), Sphipervasc project (ANR)
  • G. Osol (Univ. of Vermont, USA), Uterine artery remodeling
  • M. Mandala (Univ of Calabria, Italy), vascular remodeling in pregnancy
  • V. Nivet, UMR S-1140, Paris. Métabolisme et pathophysiologie cardiovasculaire.
  • G. Flouriot, Irset - Inserm UMR_S 1085, Pathophysiologie des récepteurs oetrogéniques.
  • Dr. Stefan Offermanns, Max Planck Institute for Heart and Lung Research Dept. of Pharmacology, Bad Nauheim, Germany. Mechanosensitve GPCRs and G-proteins.

Selected recent articles

Review articles:

  • Arnal JF, Lenfant F, Metivier R, Flouriot G, Henrion D, Adlanmerini M, Fontaine C, Gourdy P, Chambon P, Katzenellenbogen B, Katzenellenbogen J. Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications. Physiol Rev. 2017;97:1045-1087.

Research articles:

  • Guivarc'h E, Favre J, Guihot AL, Vessières E, Grimaud L, Proux C, Rivron J, Barbelivien A, Fassot C, Briet M, Lenfant F, Fontaine C, Loufrani L, Arnal JF, Henrion D. Nuclear Activation Function 2 Estrogen Receptor α Attenuates Arterial and Renal Alterations Due to Aging and Hypertension in Female Mice. J Am Heart Assoc. 2020 Mar 3;9(5):e013895
  • Chennupati R, Wirth A, Favre J, Li R, Bonnavion R, Jin YJ, Wietelmann A, Schweda F, Wettschureck N, Henrion D, Offermanns S. Myogenic vasoconstriction requires G12/G13 and LARG to maintain local and systemic vascular resistance. Elife. 2019 Sep 24;8. pii: e49374.
  • Xu J, Mathur J, Vessières V, Hammack S, Nonomura K, Favre J, Grimaud L, Petrus M, Francisco A, Li J, Lee V, Xiang FL, Mainquist JK, Cahalan SM, Orth AP, Walker JR, Ma S, Lukacs V, Bandell M, Bordone L, Laffitte B, Xu Y, Chien S, Henrion D and Patapoutian A. GPR68 Senses Flow and Is Essential for Vascular Physiology. Cell 2018;173(3):762-775.
  • Guivarc'h E, Buscato M, Guihot AL, Favre J, Vessières E, Grimaud L, Wakim J, Melhem NJ, Zahreddine R, Adlanmerini M, Loufrani L, Knauf C, Katzenellenbogen JA, Katzenellenbogen BS, Foidart JM, Gourdy P, Lenfant F, Arnal JF, *Henrion D, *Fontaine C. Predominant Role of Nuclear Versus Membrane Estrogen Receptor α in Arterial Protection: Implications for Estrogen Receptor α Modulation in Cardiovascular Prevention/Safety. J Am Heart Assoc. 2018 Jun 29;7(13). pii: e008950. *equal contribution
  • Begorre MA, Dib A, Habchi K, Guihot AL, Bourreau J, Vessieres E, Blondeau B, Loufrani L, Chabbert M, Henrion D, Fassot C. Microvascular vasodilator properties of the angiotensin II type 2 receptor in a mouse model of type 1 diabetes. Sci Rep. 2017 Mar 31;7:45625. doi: 10.1038/srep45625.
  • Abot A, Fontaine C, Buscato M, Solinhac R, Flouriot G, Fabre A, Drougard A, Rajan S, Laine M, Milon A, Muller I, Henrion D, Adlanmerini M, Valéra MC, Gompel A, Gerard C, Péqueux C, Mestdagt M, Raymond-Letron I, Knauf C, Ferriere F, Valet P, Gourdy P, Katzenellenbogen BS, Katzenellenbogen JA, Lenfant F, Greene GL, Foidart JM, Arnal JF. The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor α modulation, uncoupling nuclear and membrane activation. EMBO Mol Med. 2014;6:1328-46
  • Tarhouni K, Freidja ML, Guihot AL, Vessieres E, Grimaud L, Toutain B, Lenfant F, Arnal JF, Loufrani L, Henrion D. Role of estrogens and age in flow-mediated outward remodeling of rat mesenteric resistance arteries. Am J Physiol Heart Circ Physiol. 2014 ; 307, H504-H514
    Tarhouni K, A.L. Guihot, E. Vessières, B. Toutain, V. Procaccio, L Grimaud, L. Loufrani, F. Lenfant, JF. Arnal, D. Henrion. Determinants of flow-mediated outward remodeling in female rodents: respective roles of age, estrogens and timing. Arterioscler Thromb Vasc Biol. 2014;34:1281-9.
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