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CC BY-NC-ND 4.0 · Thromb Haemost 2021; 121(06): 741-754
DOI: 10.1055/s-0040-1721505
Endothelium and Angiogenesis

Endothelial β1 Integrin-Mediated Adaptation to Myocardial Ischemia

Carina Henning‡   *
1   Institute of Metabolic Physiology, Department of Biology, Heinrich-Heine-University, Düsseldorf, Germany
,
Anna Branopolski‡   *
1   Institute of Metabolic Physiology, Department of Biology, Heinrich-Heine-University, Düsseldorf, Germany
2   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
,
Paula Follert
1   Institute of Metabolic Physiology, Department of Biology, Heinrich-Heine-University, Düsseldorf, Germany
,
Oksana Lewandowska
1   Institute of Metabolic Physiology, Department of Biology, Heinrich-Heine-University, Düsseldorf, Germany
,
Aysel Ayhan
2   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
,
Marcel Benkhoff
2   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
,
Ulrich Flögel
3   Institute for Molecular Cardiology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
,
Malte Kelm
2   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
,
Christian Heiss    *
2   Division of Cardiology, Pulmonology, and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany
4   Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
5   Surrey and Sussex Healthcare NHS Trust, Redhill, Surrey, United Kingdom
,
Eckhard Lammert   *
1   Institute of Metabolic Physiology, Department of Biology, Heinrich-Heine-University, Düsseldorf, Germany
6   Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ)—Leibniz Center for Diabetes Research, Düsseldorf, Germany
7   German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
› Author Affiliations Funding This project was supported and funded by the Deutsche Forschungsgemeinschaft (DFG) through the SFB 1116 (“Master Switches in Cardiac Ischemia”), the SFB 974 (“Communication and Systems Relevance during Liver Damage and Regeneration”), the IRTG 1902 (“Intra- and Interorgan Communication of the Cardiovascular System”) and the Federal Ministry of Health, the Ministry of Culture and Science of North Rhine-Westphalia, and the German Center for Diabetes Research (DZD e.V.).
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Abstract

Background Short episodes of myocardial ischemia can protect from myocardial infarction. However, the role of endothelial β1 integrin in these cardioprotective ischemic events is largely unknown.

Objective In this study we investigated whether endothelial β1 integrin is required for cardiac adaptation to ischemia and protection from myocardial infarction.

Methods Here we introduced transient and permanent left anterior descending artery (LAD) occlusions in mice. We inhibited β1 integrin by intravenous injection of function-blocking antibodies and tamoxifen-induced endothelial cell (EC)-specific deletion of Itgb1. Furthermore, human ITGB1 was silenced in primary human coronary artery ECs using small interfering RNA. We analyzed the numbers of proliferating ECs and arterioles by immunohistochemistry, determined infarct size by magnetic resonance imaging (MRI) and triphenyl tetrazolium chloride staining, and analyzed cardiac function by MRI and echocardiography.

Results Transient LAD occlusions were found to increase EC proliferation and arteriole formation in the entire myocardium. These effects required β1 integrin on ECs, except for arteriole formation in the ischemic part of the myocardium. Furthermore, this integrin subunit was also relevant for basal and mechanically induced proliferation of human coronary artery ECs. Notably, β1 integrin was needed for cardioprotection induced by transient LAD occlusions, and the absence of endothelial β1 integrin resulted in impaired growth of blood vessels into the infarcted myocardium and reduced cardiac function after permanent LAD occlusion.

Conclusion We showed that endothelial β1 integrin is required for adaptation of the heart to cardiac ischemia and protection from myocardial infarction.

Keywords

endothelial β1 integrin - cardiac vascular growth - myocardial infarction - cardioprotection

* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 22 October 2020

Accepted: 28 October 2020

Article published online:
14 January 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017; 390 (10106): 1151-1210
    CrossrefPubMedGoogle Scholar
  • 2 Benjamin EJ, Virani SS, Callaway CW. et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation 2018; 137 (12) e67-e492
    CrossrefPubMedGoogle Scholar
  • 3 Cannon B. Cardiovascular disease: biochemistry to behaviour. Nature 2013; 493 (7434): S2-S3
    CrossrefPubMedGoogle Scholar
  • 4 Lavine KJ, Kovacs A, Weinheimer C, Mann DL. Repetitive myocardial ischemia promotes coronary growth in the adult mammalian heart. J Am Heart Assoc 2013; 2 (05) e000343
    CrossrefPubMedGoogle Scholar
  • 5 Gloekler S, Seiler C. Cardiology patient page. Natural bypasses can save lives. Circulation 2007; 116 (11) e340-e341
    CrossrefPubMedGoogle Scholar
  • 6 Seiler C, Stoller M, Pitt B, Meier P. The human coronary collateral circulation: development and clinical importance. Eur Heart J 2013; 34 (34) 2674-2682
    CrossrefPubMedGoogle Scholar
  • 7 Jamaiyar A, Juguilon C, Dong F. et al. Cardioprotection during ischemia by coronary collateral growth. Am J Physiol Heart Circ Physiol 2019; 316 (01) H1-H9
    CrossrefPubMedGoogle Scholar
  • 8 Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000; 6 (04) 389-395
    CrossrefPubMedGoogle Scholar
  • 9 Cochain C, Channon KM, Silvestre JS. Angiogenesis in the infarcted myocardium. Antioxid Redox Signal 2013; 18 (09) 1100-1113
    CrossrefPubMedGoogle Scholar
  • 10 Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 2016; 17 (10) 611-625
    CrossrefPubMedGoogle Scholar
  • 11 Ingber D. Integrins as mechanochemical transducers. Curr Opin Cell Biol 1991; 3 (05) 841-848
    CrossrefPubMedGoogle Scholar
  • 12 Planas-Paz L, Strilić B, Goedecke A, Breier G, Fässler R, Lammert E. Mechanoinduction of lymph vessel expansion. EMBO J 2012; 31 (04) 788-804
    CrossrefPubMedGoogle Scholar
  • 13 Ross TD, Coon BG, Yun S. et al. Integrins in mechanotransduction. Curr Opin Cell Biol 2013; 25 (05) 613-618
    CrossrefPubMedGoogle Scholar
  • 14 Sun Z, Costell M, Fässler R. Integrin activation by talin, kindlin and mechanical forces. Nat Cell Biol 2019; 21 (01) 25-31
    CrossrefPubMedGoogle Scholar
  • 15 Somanath PR, Ciocea A, Byzova TV. Integrin and growth factor receptor alliance in angiogenesis. Cell Biochem Biophys 2009; 53 (02) 53-64
    CrossrefPubMedGoogle Scholar
  • 16 Tugues S, Honjo S, König C. et al. Tetraspanin CD63 promotes vascular endothelial growth factor receptor 2-β1 integrin complex formation, thereby regulating activation and downstream signaling in endothelial cells in vitro and in vivo. J Biol Chem 2013; 288 (26) 19060-19071
    CrossrefPubMedGoogle Scholar
  • 17 Thodeti CK, Matthews B, Ravi A. et al. TRPV4 channels mediate cyclic strain-induced endothelial cell reorientation through integrin-to-integrin signaling. Circ Res 2009; 104 (09) 1123-1130
    CrossrefPubMedGoogle Scholar
  • 18 Lorenz L, Axnick J, Buschmann T. et al. Mechanosensing by β1 integrin induces angiocrine signals for liver growth and survival. Nature 2018; 562 (7725): 128-132
    CrossrefPubMedGoogle Scholar
  • 19 Lei L, Liu D, Huang Y. et al. Endothelial expression of beta1 integrin is required for embryonic vascular patterning and postnatal vascular remodeling. Mol Cell Biol 2008; 28 (02) 794-802
    CrossrefPubMedGoogle Scholar
  • 20 Tanjore H, Zeisberg EM, Gerami-Naini B, Kalluri R. Beta1 integrin expression on endothelial cells is required for angiogenesis but not for vasculogenesis. Dev Dyn 2008; 237 (01) 75-82
    CrossrefPubMedGoogle Scholar
  • 21 Carlson TR, Hu H, Braren R, Kim YH, Wang RA. Cell-autonomous requirement for beta1 integrin in endothelial cell adhesion, migration and survival during angiogenesis in mice. Development 2008; 135 (12) 2193-2202
    CrossrefPubMedGoogle Scholar
  • 22 Zovein AC, Luque A, Turlo KA. et al. Beta1 integrin establishes endothelial cell polarity and arteriolar lumen formation via a Par3-dependent mechanism. Dev Cell 2010; 18 (01) 39-51
    CrossrefPubMedGoogle Scholar
  • 23 Yamamoto H, Ehling M, Kato K. et al. Integrin β1 controls VE-cadherin localization and blood vessel stability. Nat Commun 2015; 6: 6429
    CrossrefPubMedGoogle Scholar
  • 24 Lindsey ML, Iyer RP, Zamilpa R. et al. A novel collagen matricryptin reduces left ventricular dilation post-myocardial infarction by promoting scar formation and angiogenesis. J Am Coll Cardiol 2015; 66 (12) 1364-1374
    CrossrefPubMedGoogle Scholar
  • 25 Martin K, Pritchett J, Llewellyn J. et al. PAK proteins and YAP-1 signalling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat Commun 2016; 7: 12502
    CrossrefPubMedGoogle Scholar
  • 26 Abraham S, Kogata N, Fässler R, Adams RH. Integrin beta1 subunit controls mural cell adhesion, spreading, and blood vessel wall stability. Circ Res 2008; 102 (05) 562-570
    CrossrefPubMedGoogle Scholar
  • 27 Mishina H, Watanabe K, Tamaru S. et al. Lack of phospholipase A2 receptor increases susceptibility to cardiac rupture after myocardial infarction. Circ Res 2014; 114 (03) 493-504
    CrossrefPubMedGoogle Scholar
  • 28 Li R, Wu Y, Manso AM. et al. β1 integrin gene excision in the adult murine cardiac myocyte causes defective mechanical and signaling responses. Am J Pathol 2012; 180 (03) 952-962
    CrossrefPubMedGoogle Scholar
  • 29 Okada H, Lai NC, Kawaraguchi Y. et al. Integrins protect cardiomyocytes from ischemia/reperfusion injury. J Clin Invest 2013; 123 (10) 4294-4308
    CrossrefPubMedGoogle Scholar
  • 30 Bolli R. Preconditioning: a paradigm shift in the biology of myocardial ischemia. Am J Physiol Heart Circ Physiol 2007; 292 (01) H19-H27
    CrossrefPubMedGoogle Scholar
  • 31 Bolli R, Li QH, Tang XL. et al. The late phase of preconditioning and its natural clinical application--gene therapy. Heart Fail Rev 2007; 12 (3–4): 189-199
    CrossrefPubMedGoogle Scholar
  • 32 Dawn B, Bolli R. Role of nitric oxide in myocardial preconditioning. Ann N Y Acad Sci 2002; 962: 18-41
    CrossrefPubMedGoogle Scholar
  • 33 Heusch G. Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 2015; 116 (04) 674-699
    CrossrefPubMedGoogle Scholar
  • 34 Lindsey ML, Bolli R, Canty Jr JM. et al. Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 2018; 314 (04) H812-H838
    CrossrefPubMedGoogle Scholar
  • 35 Shesely EG, Maeda N, Kim HS. et al. Elevated blood pressures in mice lacking endothelial nitric oxide synthase. Proc Natl Acad Sci U S A 1996; 93 (23) 13176-13181
    CrossrefPubMedGoogle Scholar
  • 36 Benedito R, Roca C, Sörensen I. et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 2009; 137 (06) 1124-1135
    CrossrefPubMedGoogle Scholar
  • 37 Potocnik AJ, Brakebusch C, Fässler R. Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow. Immunity 2000; 12 (06) 653-663
    CrossrefPubMedGoogle Scholar
  • 38 Bönner F, Jacoby C, Temme S. et al. Multifunctional MR monitoring of the healing process after myocardial infarction. Basic Res Cardiol 2014; 109 (05) 430
    CrossrefPubMedGoogle Scholar
  • 39 Erkens R, Kramer CM, Lückstädt W. et al. Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med 2015; 89: 906-917
    CrossrefPubMedGoogle Scholar
  • 40 Zhang H, Faber JE. De-novo collateral formation following acute myocardial infarction: dependence on CCR2+ bone marrow cells. J Mol Cell Cardiol 2015; 87: 4-16
    CrossrefPubMedGoogle Scholar
  • 41 Henning C, Branopolski A, Schuler D. et al. Requirement of β1 integrin for endothelium-dependent vasodilation and collateral formation in hindlimb ischemia. Sci Rep 2019; 9 (01) 16931
    CrossrefPubMedGoogle Scholar
  • 42 Yang B, Rizzo V. Shear stress activates eNOS at the endothelial apical surface through β1 containing integrins and caveolae. Cell Mol Bioeng 2013; 6 (03) 346-354
    CrossrefPubMedGoogle Scholar
  • 43 Xanthis I, Souilhol C, Serbanovic-Canic J. et al. β1 integrin is a sensor of blood flow direction. J Cell Sci 2019; 132 (11) jcs229542
    CrossrefPubMedGoogle Scholar
  • 44 Israeli-Rosenberg S, Manso AM, Okada H, Ross RS. Integrins and integrin-associated proteins in the cardiac myocyte. Circ Res 2014; 114 (03) 572-586
    CrossrefPubMedGoogle Scholar
  • 45 Hodgkinson CP, Gomez JA, Payne AJ. et al. Abi3bp regulates cardiac progenitor cell proliferation and differentiation. Circ Res 2014; 115 (12) 1007-1016
    CrossrefPubMedGoogle Scholar
  • 46 Krishnamurthy P, Subramanian V, Singh M, Singh K. Deficiency of beta1 integrins results in increased myocardial dysfunction after myocardial infarction. Heart 2006; 92 (09) 1309-1315
    CrossrefPubMedGoogle Scholar
  • 47 Shai SY, Harpf AE, Babbitt CJ. et al. Cardiac myocyte-specific excision of the beta1 integrin gene results in myocardial fibrosis and cardiac failure. Circ Res 2002; 90 (04) 458-464
    CrossrefPubMedGoogle Scholar
  • 48 Li L, Guan Q, Dai S, Wei W, Zhang Y. Integrin β1 increases stem cell survival and cardiac function after myocardial infarction. Front Pharmacol 2017; 8: 135
    PubMedGoogle Scholar
  • 49 Hakanpaa L, Kiss EA, Jacquemet G. et al. Targeting β1-integrin inhibits vascular leakage in endotoxemia. Proc Natl Acad Sci U S A 2018; 115 (28) E6467-E6476
    CrossrefPubMedGoogle Scholar
  • 50 van der Vorst EPC, Weber C. Novel features of monocytes and macrophages in cardiovascular biology and disease. Arterioscler Thromb Vasc Biol 2019; 39 (02) e30-e37
    PubMedGoogle Scholar
  • 51 Zernecke A, Bernhagen J, Weber C. Macrophage migration inhibitory factor in cardiovascular disease. Circulation 2008; 117 (12) 1594-1602
    CrossrefPubMedGoogle Scholar
  • 52 Mac Gabhann F, Peirce SM. Collateral capillary arterialization following arteriolar ligation in murine skeletal muscle. Microcirculation 2010; 17 (05) 333-347
    PubMedGoogle Scholar
  • 53 Das S, Goldstone AB, Wang H. et al. A unique collateral artery development program promotes neonatal heart regeneration. Cell 2019; 176 (05) 1128.e18-1142.e18
    PubMedGoogle Scholar
  • 54 Pitulescu ME, Schmidt I, Giaimo BD. et al. Dll4 and Notch signalling couples sprouting angiogenesis and artery formation. Nat Cell Biol 2017; 19 (08) 915-927
    CrossrefPubMedGoogle Scholar
  • 55 la Sala A, Pontecorvo L, Agresta A, Rosano G, Stabile E. Regulation of collateral blood vessel development by the innate and adaptive immune system. Trends Mol Med 2012; 18 (08) 494-501
    CrossrefPubMedGoogle Scholar
  • 56 Yue Y, Wang C, Benedict C. et al. Interleukin-10 deficiency alters endothelial progenitor cell-derived exosome reparative effect on myocardial repair via integrin-linked kinase enrichment. Circ Res 2020; 126 (03) 315-329
    CrossrefPubMedGoogle Scholar