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Aging-induced impaired endothelial wall shear stress mechanosensing causes arterial remodeling via JAM-A/F11R shedding by ADAM17

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Abstract

Physiological and pathological vascular remodeling is uniquely driven by mechanical forces from blood flow in which wall shear stress (WSS) mechanosensing by the vascular endothelium plays a pivotal role. This study aimed to determine the novel role for a disintegrin and metalloproteinase 17 (ADAM17) in impaired WSS mechanosensing, which was hypothesized to contribute to aging-associated abnormal vascular remodeling. Without changes in arterial blood pressure and blood flow rate, skeletal muscle resistance arteries of aged mice (30-month-old vs. 12-week-old) exhibited impaired WSS mechanosensing and displayed inward hypertrophic arterial remodeling. These vascular changes were recapitulated by in vivo confined, AAV9-mediated overexpression of ADAM17 in the resistance arteries of young mice. An aging-related increase in ADAM17 expression reduced the endothelial junction level of its cleavage substrate, junctional adhesion molecule-A/F11 receptor (JAM-A/F11R). In cultured endothelial cells subjected to steady WSS ADAM17 activation or JAM-A/F11R knockdown inhibited WSS mechanosensing. The ADAM17-activation induced, impaired WSS mechanosensing was normalized by overexpression of ADAM17 cleavage resistant, mutated JAM-AV232Y both in cultured endothelial cells and in resistance arteries of aged mice, in vivo. These data demonstrate a novel role for ADAM17 in JAM-A/F11R cleavage-mediated impaired endothelial WSS mechanosensing and subsequently developed abnormal arterial remodeling in aging. ADAM17 could prove to be a key regulator of WSS mechanosensing, whereby it can also play a role in pathological vascular remodeling in diseases.

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Data availability

We declare that the data supporting the findings of this study are available within the article and its Supplementary Information files and from the corresponding authors upon request.

References

  1. Baeyens N, Bandyopadhyay C, Coon BG, Yun S, Schwartz MA. Endothelial fluid shear stress sensing in vascular health and disease. J Clin Invest. 2016;126:821–8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Baeyens N, Larrivee B, Ola R, Hayward-Piatkowskyi B, Dubrac A, Huang B, Ross TD, Coon BG, Min E, Tsarfati M, Tong H, Eichmann A, Schwartz MA. Defective fluid shear stress mechanotransduction mediates hereditary hemorrhagic telangiectasia. J Cell Biol. 2016;214:807–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baeyens N, Nicoli S, Coon BG, Ross TD, Van den Dries K, Han J, Lauridsen HM, Mejean CO, Eichmann A, Thomas JL, Humphrey JD, Schwartz MA. Vascular remodeling is governed by a VEGFR3-dependent fluid shear stress set point. Elife. 2015;4:e04645.

  4. Bagi Z, Koller A. Lack of NO-mediation of flow-dependent arteriolar dilation in diabetes is restored by sepiapterin. J of Vascular Research. 2003;40:47–57.

    Article  CAS  Google Scholar 

  5. Bagi Z, Frangos JA, Yeh JC, White CR, Kaley G, Koller A. PECAM-1 mediates NO-dependent dilation of arterioles to high temporal gradients of shear stress. Arterioscler Thromb Vasc Biol. 2005;25:1590–5.

    Article  CAS  PubMed  Google Scholar 

  6. Bearden SE, Payne GW, Chisty A, Segal SS. Arteriolar network architecture and vasomotor function with ageing in mouse gluteus maximus muscle. J Physiol. 2004;561:535–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Beyer AM, Zinkevich N, Miller B, Liu Y, Wittenburg AL, Mitchell M, Galdieri R, Sorokin A, Gutterman DD. Transition in the mechanism of flow-mediated dilation with aging and development of coronary artery disease. Basic Res Cardiol. 2017;112:5.

    Article  PubMed  Google Scholar 

  8. Buus CL, Pourageaud F, Fazzi GE, Janssen G, Mulvany MJ, De Mey JG. Smooth muscle cell changes during flow-related remodeling of rat mesenteric resistance arteries. Circ Res. 2001;89:180–6.

    Article  CAS  PubMed  Google Scholar 

  9. Csiszar A, Ungvari Z, Edwards JG, Kaminski P, Wolin MS, Koller A, Kaley G. Aging-induced phenotypic changes and oxidative stress impair coronary arteriolar function. Circ Res. 2002;90:1159–66.

    Article  CAS  PubMed  Google Scholar 

  10. Dao HH, Essalihi R, Bouvet C, Moreau P. Evolution and modulation of age-related medial elastocalcinosis: impact on large artery stiffness and isolated systolic hypertension. Cardiovasc Res. 2005;66:307–17.

    Article  CAS  PubMed  Google Scholar 

  11. Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev. 1995;75:519–60.

    Article  CAS  PubMed  Google Scholar 

  12. Donato AJ, Machin DR, Lesniewski LA. Mechanisms of dysfunction in the aging vasculature and role in age-related disease. Circ Res. 2018;123:825–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dou H, Feher A, Davila AC, Romero MJ, Patel VS, Kamath VM, Gooz MB, Rudic RD, Lucas R, Fulton DJ, Weintraub NL, Bagi Z. Role of adipose tissue endothelial ADAM17 in age-related coronary microvascular dysfunction. Arterioscler Thromb Vasc Biol. 2017;37:1180–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ebnet K. Junctional adhesion molecules (JAMs): cell adhesion receptors with pleiotropic functions in cell physiology and development. Physiol Rev. 2017;97:1529–54.

    Article  CAS  PubMed  Google Scholar 

  15. Ebnet K, Suzuki A, Ohno S, Vestweber D. Junctional adhesion molecules (JAMs): more molecules with dual functions? J Cell Sci. 2004;117:19–29.

    Article  CAS  PubMed  Google Scholar 

  16. Erdei N, Toth A, Pasztor ET, Papp Z, Edes I, Koller A, Bagi Z. High-fat diet-induced reduction in nitric oxide-dependent arteriolar dilation in rats: role of xanthine oxidase-derived superoxide anion. Am J Physiol Heart Circ Physiol. 2006;291:H2107–15.

    Article  CAS  PubMed  Google Scholar 

  17. Garton KJ, Gough PJ, Philalay J, Wille PT, Blobel CP, Whitehead RH, Dempsey PJ, Raines EW. Stimulated shedding of vascular cell adhesion molecule 1 (VCAM-1) is mediated by tumor necrosis factor-alpha-converting enzyme (ADAM 17). J Biol Chem. 2003;278:37459–64.

    Article  CAS  PubMed  Google Scholar 

  18. Gerhard M, Roddy MA, Creager SJ, Creager MA. Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humans. Hypertension. 1996;27:849–53.

    Article  CAS  PubMed  Google Scholar 

  19. Gooz M. ADAM-17: the enzyme that does it all. Crit Rev Biochem Mol Biol. 2010;45:146–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gooz P, Gooz M, Baldys A, Hoffman S. ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis. Biochem Biophys Res Commun. 2009;380:33–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hajdu MA, Heistad DD, Siems JE, Baumbach GL. Effects of aging on mechanics and composition of cerebral arterioles in rats. Circ Res. 1990;66:1747–54.

    Article  CAS  PubMed  Google Scholar 

  22. Hall JE, Brands MW, Henegar JR. Mechanisms of hypertension and kidney disease in obesity. Ann N Y Acad Sci. 1999;892:91–107.

    Article  CAS  PubMed  Google Scholar 

  23. Heiss, C., R. Sansone, H. Karimi, M. Krabbe, D. Schuler, A. Rodriguez-Mateos, T. Kraemer, M. M. Cortese-Krott, G. G. Kuhnle, J. P. Spencer, H. Schroeter, M. W. Merx, M. Kelm, and European Union th Framework Program Flaviola Consortium. Impact of cocoa flavanol intake on age-dependent vascular stiffness in healthy men: a randomized, controlled, double-masked trial. Age (Dordr). 2015;37:9794.

    Google Scholar 

  24. Jackson DN, Moore AW, Segal SS. Blunting of rapid onset vasodilatation and blood flow restriction in arterioles of exercising skeletal muscle with ageing in male mice. J Physiol. 2010;588:2269–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kenwright DA, Thomson AJ, Hadoke PW, Anderson T, Moran CM, Gray GA, Hoskins PR. A protocol for improved measurement of arterial flow rate in preclinical ultrasound. Ultrasound Int Open. 2015;1:E46-52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ko KA, Fujiwara K, Krishnan S, Abe JI. En Face preparation of mouse blood vessels. J Vis Exp. 2017;123:e55460.

  27. Koenen RR, Pruessmeyer J, Soehnlein O, Fraemohs L, Zernecke A, Schwarz N, Reiss K, Sarabi A, Lindbom L, Hackeng TM, Weber C, Ludwig A. Regulated release and functional modulation of junctional adhesion molecule A by disintegrin metalloproteinases. Blood. 2009;113:4799–809.

    Article  CAS  PubMed  Google Scholar 

  28. Koller A, Kaley G. Endothelium regulates skeletal muscle microcirculation by a blood flow velocity-sensing mechanism. Am J Physiol. 1990;258:H916–20.

    CAS  PubMed  Google Scholar 

  29. Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol. 1991;260:H862–8.

    CAS  PubMed  Google Scholar 

  30. Laurant P, Adrian M, Berthelot A. Effect of age on mechanical properties of rat mesenteric small arteries. Can J Physiol Pharmacol. 2004;82:269–75.

    Article  CAS  PubMed  Google Scholar 

  31. Martinez-Lemus LA, Hill MA, Meininger GA. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure. Physiology (Bethesda). 2009;24:45–57.

    Google Scholar 

  32. Meschiari CA, Ero OK, Pan H, Finkel T, Lindsey ML. The impact of aging on cardiac extracellular matrix. Geroscience. 2017;39:7–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mulvany MJ. Vascular remodelling of resistance vessels: can we define this? Cardiovasc Res. 1999;41:9–13.

    Article  CAS  PubMed  Google Scholar 

  34. Ohanian J, Liao A, Forman SP, Ohanian V. Age-related remodeling of small arteries is accompanied by increased sphingomyelinase activity and accumulation of long-chain ceramides. Physiol Rep. 2014;2:e12015.

  35. Ohtsu H, Dempsey PJ, Frank GD, Brailoiu E, Higuchi S, Suzuki H, Nakashima H, Eguchi K, Eguchi S. ADAM17 mediates epidermal growth factor receptor transactivation and vascular smooth muscle cell hypertrophy induced by angiotensin II. Arterioscler Thromb Vasc Biol. 2006;26:e133–7.

    Article  PubMed  Google Scholar 

  36. Paneni F, Diaz Canestro C, Libby P, Luscher TF, Camici GG. The aging cardiovascular system: understanding it at the cellular and clinical levels. J Am Coll Cardiol. 2017;69:1952–67.

    Article  PubMed  Google Scholar 

  37. Pistea A, Bakker EN, Spaan JA, VanBavel E. Flow inhibits inward remodeling in cannulated porcine small coronary arteries. Am J Physiol Heart Circ Physiol. 2005;289:H2632–40.

    Article  CAS  PubMed  Google Scholar 

  38. Pourageaud F, De Mey JG. Structural properties of rat mesenteric small arteries after 4-wk exposure to elevated or reduced blood flow. Am J Physiol. 1997;273:H1699–706.

    CAS  PubMed  Google Scholar 

  39. Pruessmeyer J, Martin C, Hess FM, Schwarz N, Schmidt S, Kogel T, Hoettecke N, Schmidt B, Sechi A, Uhlig S, Ludwig A. A disintegrin and metalloproteinase 17 (ADAM17) mediates inflammation-induced shedding of syndecan-1 and -4 by lung epithelial cells. J Biol Chem. 2010;285:555–64.

    Article  CAS  PubMed  Google Scholar 

  40. Schaper W. Collateral circulation: past and present. Basic Res Cardiol. 2009;104:5–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Scott DW, Tolbert CE, Burridge K. Tension on JAM-A activates RhoA via GEF-H1 and p115 RhoGEF. Mol Biol Cell. 2016;27:1420–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Shipley RD, Muller-Delp JM. Aging decreases vasoconstrictor responses of coronary resistance arterioles through endothelium-dependent mechanisms. Cardiovasc Res. 2005;66:374–83.

    Article  CAS  PubMed  Google Scholar 

  43. Silvestre JS, Levy BI, Tedgui A. Mechanisms of angiogenesis and remodelling of the microvasculature. Cardiovasc Res. 2008;78:201–2.

    Article  CAS  PubMed  Google Scholar 

  44. Silvestre JS, Smadja DM, Levy BI. Postischemic revascularization: from cellular and molecular mechanisms to clinical applications. Physiol Rev. 2013;93:1743–802.

    Article  CAS  PubMed  Google Scholar 

  45. Solimando AG, Brandl A, Mattenheimer K, Graf C, Ritz M, Ruckdeschel A, Stuhmer T, Mokhtari Z, Rudelius M, Dotterweich J, Bittrich M, Desantis V, Ebert R, Trerotoli P, Frassanito MA, Rosenwald A, Vacca A, Einsele H, Jakob F, Beilhack A. JAM-A as a prognostic factor and new therapeutic target in multiple myeloma. Leukemia. 2018;32:736–43.

    Article  CAS  PubMed  Google Scholar 

  46. Sun D, Huang A, Koller A, Kaley G. Decreased arteriolar sensitivity to shear stress in adult rats is reversed by chronic exercise activity. Microcirculation. 2002;9:91–7.

    Article  CAS  PubMed  Google Scholar 

  47. Takayanagi T, Forrester SJ, Kawai T, Obama T, Tsuji T, Elliott KJ, Nuti E, Rossello A, Kwok HF, Scalia R, Rizzo V, Eguchi S. Vascular ADAM17 as a novel therapeutic target in mediating cardiovascular hypertrophy and perivascular fibrosis induced by angiotensin II. Hypertension. 2016;68:949–55.

    Article  CAS  PubMed  Google Scholar 

  48. Tkachenko E, Gutierrez E, Saikin SK, Fogelstrand P, Kim C, Groisman A, Ginsberg MH. The nucleus of endothelial cell as a sensor of blood flow direction. Biol Open. 2013;2:1007–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tornavaca O, Chia M, Dufton N, Almagro LO, Conway DE, Randi AM, Schwartz MA, Matter K, Balda MS. ZO-1 controls endothelial adherens junctions, cell-cell tension, angiogenesis, and barrier formation. J Cell Biol. 2015;208:821–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tran L, Greenwood-Van Meerveld B. Age-associated remodeling of the intestinal epithelial barrier. J Gerontol A Biol Sci Med Sci. 2013;68:1045–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tsakadze NL, Sithu SD, Sen U, English WR, Murphy G, D’Souza SE. Tumor necrosis factor-alpha-converting enzyme (TACE/ADAM-17) mediates the ectodomain cleavage of intercellular adhesion molecule-1 (ICAM-1). J Biol Chem. 2006;281:3157–64.

    Article  CAS  PubMed  Google Scholar 

  52. Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature. 2005;437:426–31.

    Article  CAS  PubMed  Google Scholar 

  53. Ungvari Z, Tarantini S, Donato AJ, Galvan V, Csiszar A. Mechanisms of vascular aging. Circ Res. 2018;123:849–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ungvari Z, Tarantini S, Nyul-Toth A, Kiss T, Yabluchanskiy A, Csipo T, Balasubramanian P, Lipecz A, Benyo Z, Csiszar A. Nrf2 dysfunction and impaired cellular resilience to oxidative stressors in the aged vasculature: from increased cellular senescence to the pathogenesis of age-related vascular diseases. Geroscience. 2019;41:727–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wawro K, Wawro M, Strzelecka M, Czarnek M, Bereta J. The role of NF-kappaB and Elk-1 in the regulation of mouse ADAM17 expression. Biol Open. 2019;8:bio039420.

  56. Wu L, Claas AM, Sarkar A, Lauffenburger DA, Han J. High-throughput protease activity cytometry reveals dose-dependent heterogeneity in PMA-mediated ADAM17 activation. Integr Biol (Camb). 2015;7:513–24.

    Article  CAS  Google Scholar 

  57. Xu H, Lu S, Ding L, Lyu L, Ma Z, Lu Q. Pulsatility index as a novel parameter for perfusion in mouse model of hindlimb ischemia. Cell Physiol Biochem. 2018;48:2114–22.

    Article  CAS  PubMed  Google Scholar 

  58. Zhou J, Li YS, Chien S. Shear stress-initiated signaling and its regulation of endothelial function. Arterioscler Thromb Vasc Biol. 2014;34:2191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by awards from the American Heart Association [20PRE35211126 to YT] and National Institutes of Health, National Institute on Aging [R01AG054651 to ZB].

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Authors and Affiliations

  1. Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    Yanna Tian, Katie Anne Fopiano, Vadym Buncha, Liwei Lang, Jessica A. Filosa, Huijuan Dou & Zsolt Bagi

  2. Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA, 30912, USA

    R. Daniel Rudic

  3. Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA

    Huijuan Dou

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  1. Yanna Tian
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  2. Katie Anne Fopiano
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Contributions

Z.B. conceptualized the project. Z.B., Y.T., H.D., K.A.F., L.L., and V.B. performed the experiments. Y.T and Z.B wrote the original draft of the manuscript. Y.T., H.D., K.A.F., V.B., L.L., R.D.R., J.A.F, and Z.B. reviewed and edited the manuscript. Z.B. supervised the research.

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Correspondence to Zsolt Bagi.

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Tian, Y., Fopiano, K.A., Buncha, V. et al. Aging-induced impaired endothelial wall shear stress mechanosensing causes arterial remodeling via JAM-A/F11R shedding by ADAM17. GeroScience 44, 349–369 (2022). https://doi.org/10.1007/s11357-021-00476-1

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