Skip to main content

Vascular Endothelial Mechanosensors in Response to Fluid Shear Stress

  • Chapter
  • First Online:
Molecular and Cellular Mechanobiology

Part of the book series: Physiology in Health and Disease ((PIHD))

Abstract

The endothelium consists of a single layer of vascular endothelial cells (ECs) and serves as a selective barrier between the blood and arteries. ECs are constantly exposed to blood flow- and pulsatile blood pressure-induced hemodynamic forces. The cells are able to convert these mechanical stimuli into biochemical signals and then transmit the signals into the cell interior to affect cellular functions. These mechanical stimuli are detected by multiple mechanosensors in ECs that activate signaling pathways through their associated adaptor proteins, eventually leading to the maintenance of vascular homeostasis or the development of the pathogenesis of vascular disorders. These mechanosensors are distributed in different parts of the ECs, including the cell membrane, cell-to-cell junctions, the cytoplasm, and the nucleus. This review attempts to bring together recent findings on these mechanosensors and presents a conceptual framework for understanding the regulation of endothelial mechanosensors in response to hemodynamic forces. With verification by in vitro and in vivo evidence, endothelial mechanosensors have been demonstrated to contribute to health and disease by regulating physiological and pathophysiological processes in response to mechanical stimuli.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 199.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • AbouAlaiwi WA, Takahashi M, Mell BR, Jones TJ, Ratnam S, Kolb RJ, Nauli SM (2009) Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ Res 104:860–869

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Alam S, Lovett DB, Dickinson RB, Roux KJ, Lele TP (2014) Nuclear forces and cell mechanosensing. Prog Mol Biol Transl Sci 126:205–215

    Article  PubMed  PubMed Central  Google Scholar 

  • Ankeny RF, Thourani VH, Weiss D, Vega JD, Taylor WR, Nerem RM, Jo H (2011) Preferential activation of smad1/5/8 on the fibrosa endothelium in calcified human aortic valves—association with low bmp antagonists and smad6. PLoS One 6, e20969

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ayalon O, Sabanai H, Lampugnani MG, Dejana E, Geiger B (1994) Spatial and temporal relationships between cadherins and pecam-1 in cell-cell junctions of human endothelial cells. J Cell Biol 126:247–258

    Article  CAS  PubMed  Google Scholar 

  • Baeyens N, Mulligan-Kehoe MJ, Corti F, Simon DD, Ross TD, Rhodes JM, Wang TZ, Mejean CO, Simons M, Humphrey J, Schwartz MA (2014) Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proc Natl Acad Sci U S A 111:17308–17313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Barakat AI, Leaver EV, Pappone PA, Davies PF (1999) A flow-activated chloride-selective membrane current in vascular endothelial cells. Circ Res 85:820–828

    Article  CAS  PubMed  Google Scholar 

  • Bernfield M, Gotte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J, Zako M (1999) Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem 68:729–777

    Article  CAS  PubMed  Google Scholar 

  • Bhullar IS, Li YS, Miao H, Zandi E, Kim M, Shyy JY, Chien S (1998) Fluid shear stress activation of ikappaB kinase is integrin-dependent. J Biol Chem 273:30544–30549

    Article  CAS  PubMed  Google Scholar 

  • Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano D, Sadeghi H, Stefani E, Birnbaumer M (1996) On the molecular basis and regulation of cellular capacitative calcium entry: roles for trp proteins. Proc Natl Acad Sci U S A 93:15195–15202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brakemeier S, Kersten A, Eichler I, Grgic I, Zakrzewicz A, Hopp H, Kohler R, Hoyer J (2003) Shear stress-induced up-regulation of the intermediate-conductance ca(2+)-activated k(+) channel in human endothelium. Cardiovasc Res 60:488–496

    Article  CAS  PubMed  Google Scholar 

  • Butcher DT, Alliston T, Weaver VM (2009) A tense situation: forcing tumour progression. Nat Rev Cancer 9:108–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bystrevskaya VB, Lichkun VV, Krushinsky AV, Smirnov VN (1992) Centriole modification in human aortic endothelial cells. J Struct Biol 109:1–12

    Article  CAS  PubMed  Google Scholar 

  • Campbell ID, Humphries MJ (2011) Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 3, pii: a004994

    Article  CAS  Google Scholar 

  • Canessa CM, Schild L, Buell G, Thorens B, Gautschi I, Horisberger JD, Rossier BC (1994) Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits. Nature 367:463–467

    Article  CAS  PubMed  Google Scholar 

  • Carmeliet P, Lampugnani MG, Moons L, Breviario F, Compernolle V, Bono F, Balconi G, Spagnuolo R, Oosthuyse B, Dewerchin M, Zanetti A, Angellilo A, Mattot V, Nuyens D, Lutgens E, Clotman F, de Ruiter MC, Gittenberger-de Groot A, Poelmann R, Lupu F, Herbert JM, Collen D, Dejana E (1999) Targeted deficiency or cytosolic truncation of the VE-cadherin gene in mice impairs VEGF-mediated endothelial survival and angiogenesis. Cell 98:147–157

    Article  CAS  PubMed  Google Scholar 

  • Chachisvilis M, Zhang YL, Frangos JA (2006) G protein-coupled receptors sense fluid shear stress in endothelial cells. Proc Natl Acad Sci U S A 103:15463–15468

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chambliss AB, Khatau SB, Erdenberger N, Robinson DK, Hodzic D, Longmore GD, Wirtz D (2013) The LINC-anchored actin cap connects the extracellular milieu to the nucleus for ultrafast mechanotransduction. Sci Rep 3:1087

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Chancellor TJ, Lee J, Thodeti CK, Lele T (2010) Actomyosin tension exerted on the nucleus through nesprin-1 connections influences endothelial cell adhesion, migration, and cyclic strain-induced reorientation. Biophys J 99:115–123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chatterjee S, Al-Mehdi AB, Levitan I, Stevens T, Fisher AB (2003) Shear stress increases expression of a katp channel in rat and bovine pulmonary vascular endothelial cells. Am J Physiol Cell Physiol 285:C959–C967

    Article  CAS  PubMed  Google Scholar 

  • Chen KD, Li YS, Kim M, Li S, Yuan S, Chien S, Shyy JY (1999) Mechanotransduction in response to shear stress. Roles of receptor tyrosine kinases, integrins, and shc. J Biol Chem 274:18393–18400

    Article  CAS  PubMed  Google Scholar 

  • Chien S (2007) Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am J Physiol Heart Circ Physiol 292:H1209–H1224

    Article  CAS  PubMed  Google Scholar 

  • Chiu YJ, McBeath E, Fujiwara K (2008) Mechanotransduction in an extracted cell model: Fyn drives stretch- and flow-elicited pecam-1 phosphorylation. J Cell Biol 182:753–763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crisp M, Liu Q, Roux K, Rattner JB, Shanahan C, Burke B, Stahl PD, Hodzic D (2006) Coupling of the nucleus and cytoplasm: role of the LINC complex. J Cell Biol 172:41–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dahl KN, Engler AJ, Pajerowski JD, Discher DE (2005) Power-law rheology of isolated nuclei with deformation mapping of nuclear substructures. Biophys J 89:2855–2864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davies PF (2009) Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 6:16–26

    Article  CAS  PubMed  Google Scholar 

  • Deguchi S, Maeda K, Ohashi T, Sato M (2005) Flow-induced hardening of endothelial nucleus as an intracellular stress-bearing organelle. J Biomech 38:1751–1759

    Article  PubMed  Google Scholar 

  • Dejana E (2004) Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 5:261–270

    Article  CAS  PubMed  Google Scholar 

  • Dejana E, Corada M, Lampugnani MG (1995) Endothelial cell-to-cell junctions. FASEB J 9:910–918

    CAS  PubMed  Google Scholar 

  • dela Paz NG, Melchior B, Shayo FY, Frangos JA (2014) Heparan sulfates mediate the interaction between platelet endothelial cell adhesion molecule-1 (pecam-1) and the galphaq/11 subunits of heterotrimeric g proteins. J Biol Chem 289:7413–7424

    Article  CAS  Google Scholar 

  • Doyle DA (2004) Molecular insights into ion channel function (review). Mol Membr Biol 21:221–225

    Article  CAS  PubMed  Google Scholar 

  • Drummond IA (1812) Polycystins, focal adhesions and extracellular matrix interactions. Biochim Biophys Acta 2011:1322–1326

    Google Scholar 

  • Du J, Ma X, Shen B, Huang Y, Birnbaumer L, Yao X (2014) Trpv4, trpc1, and trpp2 assemble to form a flow-sensitive heteromeric channel. FASEB J 28:4677–4685

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dyer LA, Pi X, Patterson C (2014) The role of BMPs in endothelial cell function and dysfunction. Trends Endocrinol Metab 25:472–480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ebong EE, Macaluso FP, Spray DC, Tarbell JM (2011) Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler Thromb Vasc Biol 31:1908–1915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egorova AD, Khedoe PP, Goumans MJ, Yoder BK, Nauli SM, ten Dijke P, Poelmann RE, Hierck BP (2011) Lack of primary cilia primes shear-induced endothelial-to-mesenchymal transition. Circ Res 108:1093–1101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egorova AD, van der Heiden K, Poelmann RE, Hierck BP (2012) Primary cilia as biomechanical sensors in regulating endothelial function. Differentiation 83:S56–S61

    Article  CAS  PubMed  Google Scholar 

  • Elrayess MA, Webb KE, Flavell DM, Syvanne M, Taskinen MR, Frick MH, Nieminen MS, Kesaniemi YA, Pasternack A, Jukema JW, Kastelein JJ, Zwinderman AH, Humphries SE (2003) A novel functional polymorphism in the pecam-1 gene (53g > a) is associated with progression of atherosclerosis in the LOCAT and REGRESS studies. Atherosclerosis 168:131–138

    Article  CAS  PubMed  Google Scholar 

  • Elrayess MA, Webb KE, Bellingan GJ, Whittall RA, Kabir J, Hawe E, Syvanne M, Taskinen MR, Frick MH, Nieminen MS, Kesaniemi YA, Pasternack A, Miller GJ, Humphries SE (2004) R643g polymorphism in pecam-1 influences transendothelial migration of monocytes and is associated with progression of CHD and CHD events. Atherosclerosis 177:127–135

    Article  CAS  PubMed  Google Scholar 

  • Falcone JC, Kuo L, Meininger GA (1993) Endothelial cell calcium increases during flow-induced dilation in isolated arterioles. Am J Physiol 264:H653–H659

    CAS  PubMed  Google Scholar 

  • Fedorchak GR, Kaminski A, Lammerding J (2014) Cellular mechanosensing: getting to the nucleus of it all. Prog Biophys Mol Biol 115:76–92

    Article  PubMed  PubMed Central  Google Scholar 

  • Florian JA, Kosky JR, Ainslie K, Pang Z, Dull RO, Tarbell JM (2003) Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ Res 93:e136–e142

    Article  CAS  PubMed  Google Scholar 

  • Forsyth SE, Hoger A, Hoger JH (1997) Molecular cloning and expression of a bovine endothelial inward rectifier potassium channel. FEBS Lett 409:277–282

    Article  CAS  PubMed  Google Scholar 

  • Fu BM, Tarbell JM (2013) Mechano-sensing and transduction by endothelial surface glycocalyx: composition, structure, and function. Wiley Interdiscip Rev Syst Biol Med 5:381–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujioka K, Azuma N, Kito H, Gahtan V, Esato K, Sumpio BE (2000) Role of caveolin in hemodynamic force-mediated endothelial changes. J Surg Res 92:7–10

    Article  CAS  PubMed  Google Scholar 

  • Gautam M, Gojova A, Barakat AI (2006a) Flow-activated ion channels in vascular endothelium. Cell Biochem Biophys 46:277–284

    Article  CAS  PubMed  Google Scholar 

  • Gautam M, Shen Y, Thirkill TL, Douglas GC, Barakat AI (2006b) Flow-activated chloride channels in vascular endothelium. Shear stress sensitivity, desensitization dynamics, and physiological implications. J Biol Chem 281:36492–36500

    Article  CAS  PubMed  Google Scholar 

  • Geiger B, Spatz JP, Bershadsky AD (2009) Environmental sensing through focal adhesions. Nat Rev Mol Cell Biol 10:21–33

    Article  CAS  PubMed  Google Scholar 

  • Glass R, Burnstock G (2001) Immunohistochemical identification of cells expressing atp-gated cation channels (p2x receptors) in the adult rat thyroid. J Anat 198:569–579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goehring NW, Grill SW (2013) Cell polarity: mechanochemical patterning. Trends Cell Biol 23:72–80

    Article  CAS  PubMed  Google Scholar 

  • Goel R, Schrank BR, Arora S, Boylan B, Fleming B, Miura H, Newman PJ, Molthen RC, Newman DK (2008) Site-specific effects of pecam-1 on atherosclerosis in ldl receptor-deficient mice. Arterioscler Thromb Vasc Biol 28:1996–2002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goetz JG, Steed E, Ferreira RR, Roth S, Ramspacher C, Boselli F, Charvin G, Liebling M, Wyart C, Schwab Y, Vermot J (2014) Endothelial cilia mediate low flow sensing during zebrafish vascular development. Cell Rep 6:799–808

    Article  CAS  PubMed  Google Scholar 

  • Gudi SR, Clark CB, Frangos JA (1996) Fluid flow rapidly activates g proteins in human endothelial cells. Involvement of g proteins in mechanochemical signal transduction. Circ Res 79:834–839

    Article  CAS  PubMed  Google Scholar 

  • Gudi S, Nolan JP, Frangos JA (1998) Modulation of gtpase activity of g proteins by fluid shear stress and phospholipid composition. Proc Natl Acad Sci U S A 95:2515–2519

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gudi S, Huvar I, White CR, McKnight NL, Dusserre N, Boss GR, Frangos JA (2003) Rapid activation of ras by fluid flow is mediated by galpha(q) and gbetagamma subunits of heterotrimeric g proteins in human endothelial cells. Arterioscler Thromb Vasc Biol 23:994–1000

    Article  CAS  PubMed  Google Scholar 

  • Hahn C, Schwartz MA (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10:53–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen CG, Nichols BJ (2010) Exploring the caves: cavins, caveolins and caveolae. Trends Cell Biol 20:177–186

    Article  CAS  PubMed  Google Scholar 

  • Hartmannsgruber V, Heyken WT, Kacik M, Kaistha A, Grgic I, Harteneck C, Liedtke W, Hoyer J, Kohler R (2007) Arterial response to shear stress critically depends on endothelial trpv4 expression. PLoS One 2, e827

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Helmke BP, Davies PF (2002) The cytoskeleton under external fluid mechanical forces: Hemodynamic forces acting on the endothelium. Ann Biomed Eng 30:284–296

    Article  PubMed  Google Scholar 

  • Helmke BP, Goldman RD, Davies PF (2000) Rapid displacement of vimentin intermediate filaments in living endothelial cells exposed to flow. Circ Res 86:745–752

    Article  CAS  PubMed  Google Scholar 

  • Hoger JH, Ilyin VI, Forsyth S, Hoger A (2002) Shear stress regulates the endothelial kir2.1 ion channel. Proc Natl Acad Sci U S A 99:7780–7785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huveneers S, Oldenburg J, Spanjaard E, van der Krogt G, Grigoriev I, Akhmanova A, Rehmann H, de Rooij J (2012) Vinculin associates with endothelial VE-cadherin junctions to control force-dependent remodeling. J Cell Biol 196:641–652

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hynes RO (1999) Cell adhesion: old and new questions. Trends Cell Biol 9:M33–M37

    Article  CAS  PubMed  Google Scholar 

  • Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE (1997) Tensegrity: the architectural basis of cellular mechanotransduction. Annu Rev Physiol 59:575–599

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE (2003a) Tensegrity I. Cell structure and hierarchical systems biology. J Cell Sci 116:1157–1173

    Article  CAS  PubMed  Google Scholar 

  • Ingber DE (2003b) Tensegrity II. How structural networks influence cellular information processing networks. J Cell Sci 116:1397–1408

    Article  CAS  PubMed  Google Scholar 

  • Iomini C, Tejada K, Mo W, Vaananen H, Piperno G (2004) Primary cilia of human endothelial cells disassemble under laminar shear stress. J Cell Biol 164:811–817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jaalouk DE, Lammerding J (2009) Mechanotransduction gone awry. Nat Rev Mol Cell Biol 10:63–73

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jackson DE, Ward CM, Wang R, Newman PJ (1997) The protein-tyrosine phosphatase shp-2 binds platelet/endothelial cell adhesion molecule-1 (pecam-1) and forms a distinct signaling complex during platelet aggregation. Evidence for a mechanistic link between pecam-1- and integrin-mediated cellular signaling. J Biol Chem 272:6986–6993

    Article  CAS  PubMed  Google Scholar 

  • Jin ZG, Ueba H, Tanimoto T, Lungu AO, Frame MD, Berk BC (2003) Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ Res 93:354–363

    Article  CAS  PubMed  Google Scholar 

  • Jow F, Numann R (1999) Fluid flow modulates calcium entry and activates membrane currents in cultured human aortic endothelial cells. J Membr Biol 171:127–139

    Article  CAS  PubMed  Google Scholar 

  • Kim DH, Chambliss AB, Wirtz D (2013) The multi-faceted role of the actin cap in cellular mechanosensation and mechanotransduction. Soft Matter 9:5516–5523

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kohler R, Heyken WT, Heinau P, Schubert R, Si H, Kacik M, Busch C, Grgic I, Maier T, Hoyer J (2006) Evidence for a functional role of endothelial transient receptor potential v4 in shear stress-induced vasodilatation. Arterioscler Thromb Vasc Biol 26:1495–1502

    Article  PubMed  CAS  Google Scholar 

  • Koo A, Dewey CF Jr, Garcia-Cardena G (2013) Hemodynamic shear stress characteristic of atherosclerosis-resistant regions promotes glycocalyx formation in cultured endothelial cells. Am J Physiol Cell Physiol 304:C137–C146

    Article  CAS  PubMed  Google Scholar 

  • Kuchan MJ, Frangos JA (1994) Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am J Physiol 266:C628–C636

    CAS  PubMed  Google Scholar 

  • Kuchan MJ, Jo H, Frangos JA (1994) Role of g proteins in shear stress-mediated nitric oxide production by endothelial cells. Am J Physiol 267:C753–C758

    CAS  PubMed  Google Scholar 

  • Lampugnani MG, Corada M, Caveda L, Breviario F, Ayalon O, Geiger B, Dejana E (1995) The molecular organization of endothelial cell to cell junctions: differential association of plakoglobin, beta-catenin, and alpha-catenin with vascular endothelial cadherin (VE-cadherin). J Cell Biol 129:203–217

    Article  CAS  PubMed  Google Scholar 

  • Li S, Kim M, Hu YL, Jalali S, Schlaepfer DD, Hunter T, Chien S, Shyy JY (1997) Fluid shear stress activation of focal adhesion kinase. Linking to mitogen-activated protein kinases. J Biol Chem 272:30455–30462

    Article  CAS  PubMed  Google Scholar 

  • Li YS, Haga JH, Chien S (2005) Molecular basis of the effects of shear stress on vascular endothelial cells. J Biomech 38:1949–1971

    Article  PubMed  Google Scholar 

  • Lieu DK, Pappone PA, Barakat AI (2004) Differential membrane potential and ion current responses to different types of shear stress in vascular endothelial cells. Am J Physiol Cell Physiol 286:C1367–C1375

    Article  CAS  PubMed  Google Scholar 

  • Liu CL, Huang Y, Ngai CY, Leung YK, Yao XQ (2006) Trpc3 is involved in flow- and bradykinin-induced vasodilation in rat small mesenteric arteries. Acta Pharmacol Sin 27:981–990

    Article  CAS  PubMed  Google Scholar 

  • Lombardi ML, Lammerding J (2011) Keeping the LINC: the importance of nucleocytoskeletal coupling in intracellular force transmission and cellular function. Biochem Soc Trans 39:1729–1734

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lombardi ML, Jaalouk DE, Shanahan CM, Burke B, Roux KJ, Lammerding J (2011) The interaction between nesprins and sun proteins at the nuclear envelope is critical for force transmission between the nucleus and cytoskeleton. J Biol Chem 286:26743–26753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luxton GW, Gomes ER, Folker ES, Worman HJ, Gundersen GG (2011) Tan lines: a novel nuclear envelope structure involved in nuclear positioning. Nucleus 2:173–181

    Article  PubMed  PubMed Central  Google Scholar 

  • Maniotis AJ, Chen CS, Ingber DE (1997) Demonstration of mechanical connections between integrins, cytoskeletal filaments, and nucleoplasm that stabilize nuclear structure. Proc Natl Acad Sci U S A 94:849–854

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Masuda M, Fujiwara K (1993) The biased lamellipodium development and microtubule organizing center position in vascular endothelial cells migrating under the influence of fluid flow. Biol Cell 77:237–245

    Article  CAS  PubMed  Google Scholar 

  • McCue S, Dajnowiec D, Xu F, Zhang M, Jackson MR, Langille BL (2006) Shear stress regulates forward and reverse planar cell polarity of vascular endothelium in vivo and in vitro. Circ Res 98:939–946

    Article  CAS  PubMed  Google Scholar 

  • McGlashan SR, Jensen CG, Poole CA (2006) Localization of extracellular matrix receptors on the chondrocyte primary cilium. J Histochem Cytochem 54:1005–1014

    Article  CAS  PubMed  Google Scholar 

  • Miyazono K, Maeda S, Imamura T (2005) Bmp receptor signaling: transcriptional targets, regulation of signals, and signaling cross-talk. Cytokine Growth Factor Rev 16:251–263

    Article  CAS  PubMed  Google Scholar 

  • Moccia F, Villa A, Tanzi F (2000) Flow-activated Na(+)and K(+)current in cardiac microvascular endothelial cells. J Mol Cell Cardiol 32:1589–1593

    Article  CAS  PubMed  Google Scholar 

  • Montell C (2001) Physiology, phylogeny, and functions of the trp superfamily of cation channels. Sci STKE 2001:re1

    CAS  PubMed  Google Scholar 

  • Moon JJ, Matsumoto M, Patel S, Lee L, Guan JL, Li S (2005) Role of cell surface heparan sulfate proteoglycans in endothelial cell migration and mechanotransduction. J Cell Physiol 203:166–176

    Article  CAS  PubMed  Google Scholar 

  • Morgan JT, Pfeiffer ER, Thirkill TL, Kumar P, Peng G, Fridolfsson HN, Douglas GC, Starr DA, Barakat AI (2011) Nesprin-3 regulates endothelial cell morphology, perinuclear cytoskeletal architecture, and flow-induced polarization. Mol Biol Cell 22:4324–4334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mulivor AW, Lipowsky HH (2009) Inhibition of glycan shedding and leukocyte-endothelial adhesion in postcapillary venules by suppression of matrixmetalloprotease activity with doxycycline. Microcirculation 16:657–666

    Article  CAS  PubMed  Google Scholar 

  • Nakao M, Ono K, Fujisawa S, Iijima T (1999) Mechanical stress-induced Ca2+ entry and Cl- current in cultured human aortic endothelial cells. Am J Physiol 276:C238–C249

    CAS  PubMed  Google Scholar 

  • Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129–137

    Article  CAS  PubMed  Google Scholar 

  • Nauli SM, Kawanabe Y, Kaminski JJ, Pearce WJ, Ingber DE, Zhou J (2008) Endothelial cilia are fluid shear sensors that regulate calcium signaling and nitric oxide production through polycystin-1. Circulation 117:1161–1171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Neves SR, Ram PT, Iyengar R (2002) G protein pathways. Science 296:1636–1639

    Article  CAS  PubMed  Google Scholar 

  • Newman PJ, Berndt MC, Gorski J, White GC 2nd, Lyman S, Paddock C, Muller WA (1990) Pecam-1 (cd31) cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 247:1219–1222

    Article  CAS  PubMed  Google Scholar 

  • Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Physiol Rev 81:1415–1459

    CAS  PubMed  Google Scholar 

  • Nilius B, Droogmans G, Wondergem R (2003) Transient receptor potential channels in endothelium: solving the calcium entry puzzle? Endothelium 10:5–15

    Article  CAS  PubMed  Google Scholar 

  • Noria S, Cowan DB, Gotlieb AI, Langille BL (1999) Transient and steady-state effects of shear stress on endothelial cell adherens junctions. Circ Res 85:504–514

    Article  CAS  PubMed  Google Scholar 

  • North RA (2002) Molecular physiology of p2x receptors. Physiol Rev 82:1013–1067

    Article  CAS  PubMed  Google Scholar 

  • Numata T, Shimizu T, Okada Y (2007) Direct mechano-stress sensitivity of trpm7 channel. Cell Physiol Biochem 19:1–8

    Article  CAS  PubMed  Google Scholar 

  • Oancea E, Wolfe JT, Clapham DE (2006) Functional trpm7 channels accumulate at the plasma membrane in response to fluid flow. Circ Res 98:245–253

    Article  CAS  PubMed  Google Scholar 

  • Ohno M, Gibbons GH, Dzau VJ, Cooke JP (1993) Shear stress elevates endothelial cGMP. Role of a potassium channel and g protein coupling. Circulation 88:193–197

    Article  CAS  PubMed  Google Scholar 

  • Okamoto T, Schlegel A, Scherer PE, Lisanti MP (1998) Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J Biol Chem 273:5419–5422

    Article  CAS  PubMed  Google Scholar 

  • Okuda M, Takahashi M, Suero J, Murry CE, Traub O, Kawakatsu H, Berk BC (1999) Shear stress stimulation of p130(cas) tyrosine phosphorylation requires calcium-dependent c-src activation. J Biol Chem 274:26803–26809

    Article  CAS  PubMed  Google Scholar 

  • Olesen SP, Clapham DE, Davies PF (1988) Haemodynamic shear stress activates a k+ current in vascular endothelial cells. Nature 331:168–170

    Article  CAS  PubMed  Google Scholar 

  • Osawa M, Masuda M, Kusano K, Fujiwara K (2002) Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule? J Cell Biol 158:773–785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Osmanagic-Myers S, Dechat T, Foisner R (2015) Lamins at the crossroads of mechanosignaling. Genes Dev 29:225–237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Otte LA, Bell KS, Loufrani L, Yeh JC, Melchior B, Dao DN, Stevens HY, White CR, Frangos JA (2009) Rapid changes in shear stress induce dissociation of a g alpha(q/11)-platelet endothelial cell adhesion molecule-1 complex. J Physiol 587:2365–2373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park H, Go YM, Darji R, Choi JW, Lisanti MP, Maland MC, Jo H (2000) Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase. Am J Physiol Heart Circ Physiol 278:H1285–H1293

    CAS  PubMed  Google Scholar 

  • Parton RG (1996) Caveolae and caveolins. Curr Opin Cell Biol 8:542–548

    Article  CAS  PubMed  Google Scholar 

  • Paszek MJ, Boettiger D, Weaver VM, Hammer DA (2009) Integrin clustering is driven by mechanical resistance from the glycocalyx and the substrate. PLoS Comput Biol 5, e1000604

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Pazour GJ, Witman GB (2003) The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol 15:105–110

    Article  CAS  PubMed  Google Scholar 

  • Pedersen SF, Owsianik G, Nilius B (2005) Trp channels: an overview. Cell Calcium 38:233–252

    Article  CAS  PubMed  Google Scholar 

  • Poh YC, Shevtsov SP, Chowdhury F, Wu DC, Na S, Dundr M, Wang N (2012) Dynamic force-induced direct dissociation of protein complexes in a nuclear body in living cells. Nat Commun 3:866

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Radel C, Rizzo V (2005) Integrin mechanotransduction stimulates caveolin-1 phosphorylation and recruitment of Csk to mediate actin reorganization. Am J Physiol Heart Circ Physiol 288:H936–H945

    Article  CAS  PubMed  Google Scholar 

  • Ray FR, Huang W, Slater M, Barden JA (2002) Purinergic receptor distribution in endothelial cells in blood vessels: a basis for selection of coronary artery grafts. Atherosclerosis 162:55–61

    Article  CAS  PubMed  Google Scholar 

  • Romanenko VG, Davies PF, Levitan I (2002) Dual effect of fluid shear stress on volume-regulated anion current in bovine aortic endothelial cells. Am J Physiol Cell Physiol 282:C708–C718

    Article  CAS  PubMed  Google Scholar 

  • Rubanyi GM, Romero JC, Vanhoutte PM (1986) Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250:H1145–H1149

    CAS  PubMed  Google Scholar 

  • Runnels LW, Yue L, Clapham DE (2001) Trp-plik, a bifunctional protein with kinase and ion channel activities. Science 291:1043–1047

    Article  CAS  PubMed  Google Scholar 

  • Schwartz MA, Ginsberg MH (2002) Networks and crosstalk: integrin signalling spreads. Nat Cell Biol 4:E65–E68

    Article  CAS  PubMed  Google Scholar 

  • Schwarz G, Droogmans G, Nilius B (1992) Shear stress induced membrane currents and calcium transients in human vascular endothelial cells. Pflugers Arch 421:394–396

    Article  CAS  PubMed  Google Scholar 

  • Shay-Salit A, Shushy M, Wolfovitz E, Yahav H, Breviario F, Dejana E, Resnick N (2002) Vegf receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci U S A 99:9462–9467

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shyy JY, Chien S (1997) Role of integrins in cellular responses to mechanical stress and adhesion. Curr Opin Cell Biol 9:707–713

    Article  CAS  PubMed  Google Scholar 

  • Shyy JY, Chien S (2002) Role of integrins in endothelial mechanosensing of shear stress. Circ Res 91:769–775

    Article  CAS  PubMed  Google Scholar 

  • Sosa BA, Rothballer A, Kutay U, Schwartz TU (2012) LINC complexes form by binding of three KASH peptides to domain interfaces of trimeric sun proteins. Cell 149:1035–1047

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sowa G (2012) Caveolae, caveolins, cavins, and endothelial cell function: new insights. Front Physiol 2:120

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stevens HY, Melchior B, Bell KS, Yun S, Yeh JC, Frangos JA (2008) Pecam-1 is a critical mediator of atherosclerosis. Dis Model Mech 1:175–181, discussion 179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun D, Huang A, Koller A, Kaley G (2001) Endothelial k(ca) channels mediate flow-dependent dilation of arterioles of skeletal muscle and mesentery. Microvasc Res 61:179–186

    Article  CAS  PubMed  Google Scholar 

  • Sun RJ, Muller S, Stoltz JF, Wang X (2002) Shear stress induces caveolin-1 translocation in cultured endothelial cells. Eur Biophys J 30:605–611

    Article  CAS  PubMed  Google Scholar 

  • Swift J, Ivanovska IL, Buxboim A, Harada T, Dingal PC, Pinter J, Pajerowski JD, Spinler KR, Shin JW, Tewari M, Rehfeldt F, Speicher DW, Discher DE (2013) Nuclear lamin-a scales with tissue stiffness and enhances matrix-directed differentiation. Science 341:1240104

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Tai LK, Okuda M, Abe J, Yan C, Berk BC (2002) Fluid shear stress activates proline-rich tyrosine kinase via reactive oxygen species-dependent pathway. Arterioscler Thromb Vasc Biol 22:1790–1796

    Article  CAS  PubMed  Google Scholar 

  • Takagi J, Petre BM, Walz T, Springer TA (2002) Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110:599–611

    Article  CAS  PubMed  Google Scholar 

  • Tarbell JM, Pahakis MY (2006) Mechanotransduction and the glycocalyx. J Intern Med 259:339–350

    Article  CAS  PubMed  Google Scholar 

  • Thi MM, Tarbell JM, Weinbaum S, Spray DC (2004) The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: a “bumper-car” model. Proc Natl Acad Sci U S A 101:16483–16488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas CH, Collier JH, Sfeir CS, Healy KE (2002) Engineering gene expression and protein synthesis by modulation of nuclear shape. Proc Natl Acad Sci U S A 99:1972–1977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tkachenko E, Gutierrez E, Saikin SK, Fogelstrand P, Kim C, Groisman A, Ginsberg MH (2013) The nucleus of endothelial cell as a sensor of blood flow direction. Biol Open 2:1007–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tolbert CE, Thompson PM, Superfine R, Burridge K, Campbell SL (2014) Phosphorylation at y1065 in vinculin mediates actin bundling, cell spreading, and mechanical responses to force. Biochemistry 53:5526–5536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Trebak M, Vazquez G, Bird GS, Putney JW Jr (2003) The trpc3/6/7 subfamily of cation channels. Cell Calcium 33:451–461

    Article  CAS  PubMed  Google Scholar 

  • Tsuruta D, Jones JC (2003) The vimentin cytoskeleton regulates focal contact size and adhesion of endothelial cells subjected to shear stress. J Cell Sci 116:4977–4984

    Article  CAS  PubMed  Google Scholar 

  • Tzima E, del Pozo MA, Shattil SJ, Chien S, Schwartz MA (2001) Activation of integrins in endothelial cells by fluid shear stress mediates rho-dependent cytoskeletal alignment. EMBO J 20:4639–4647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tzima E, Kiosses WB, del Pozo MA, Schwartz MA (2003) Localized cdc42 activation, detected using a novel assay, mediates microtubule organizing center positioning in endothelial cells in response to fluid shear stress. J Biol Chem 278:31020–31023

    Article  CAS  PubMed  Google Scholar 

  • Tzima E, Irani-Tehrani M, Kiosses WB, Dejana E, Schultz DA, Engelhardt B, Cao G, DeLisser H, Schwartz MA (2005) A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437:426–431

    Article  CAS  PubMed  Google Scholar 

  • Van der Heiden K, Hierck BP, Krams R, de Crom R, Cheng C, Baiker M, Pourquie MJ, Alkemade FE, DeRuiter MC, Gittenberger-de Groot AC, Poelmann RE (2008) Endothelial primary cilia in areas of disturbed flow are at the base of atherosclerosis. Atherosclerosis 196:542–550

    Article  PubMed  CAS  Google Scholar 

  • Voyvodic PL, Min D, Liu R, Williams E, Chitalia V, Dunn AK, Baker AB (2014) Loss of syndecan-1 induces a pro-inflammatory phenotype in endothelial cells with a dysregulated response to atheroprotective flow. J Biol Chem 289:9547–9559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Miao H, Li S, Chen KD, Li YS, Yuan S, Shyy JY, Chien S (2002) Interplay between integrins and flk-1 in shear stress-induced signaling. Am J Physiol Cell Physiol 283:C1540–C1547

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Chang J, Li YC, Li YS, Shyy JY, Chien S (2004) Shear stress and vegf activate ikk via the flk-1/cbl/akt signaling pathway. Am J Physiol Heart Circ Physiol 286:H685–H692

    Article  CAS  PubMed  Google Scholar 

  • Wang S, Meng F, Mohan S, Champaneri B, Gu Y (2009) Functional ENaC channels expressed in endothelial cells: a new candidate for mediating shear force. Microcirculation 16:276–287

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Shi Z, Jiao S, Chen C, Wang H, Liu G, Wang Q, Zhao Y, Greene MI, Zhou Z (2012) Structural insights into SUN-KASH complexes across the nuclear envelope. Cell Res 22:1440–1452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe H, Davis JB, Smart D, Jerman JC, Smith GD, Hayes P, Vriens J, Cairns W, Wissenbach U, Prenen J, Flockerzi V, Droogmans G, Benham CD, Nilius B (2002) Activation of trpv4 channels (hvrl-2/mtrp12) by phorbol derivatives. J Biol Chem 277:13569–13577

    Article  CAS  PubMed  Google Scholar 

  • Weinbaum S, Tarbell JM, Damiano ER (2007) The structure and function of the endothelial glycocalyx layer. Annu Rev Biomed Eng 9:121–167

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Korenaga R, Kamiya A, Qi Z, Sokabe M, Ando J (2000a) P2x(4) receptors mediate atp-induced calcium influx in human vascular endothelial cells. Am J Physiol Heart Circ Physiol 279:H285–H292

    CAS  PubMed  Google Scholar 

  • Yamamoto K, Korenaga R, Kamiya A, Ando J (2000b) Fluid shear stress activates ca(2+) influx into human endothelial cells via p2x4 purinoceptors. Circ Res 87:385–391

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto K, Sokabe T, Matsumoto T, Yoshimura K, Shibata M, Ohura N, Fukuda T, Sato T, Sekine K, Kato S, Isshiki M, Fujita T, Kobayashi M, Kawamura K, Masuda H, Kamiya A, Ando J (2006) Impaired flow-dependent control of vascular tone and remodeling in p2x4-deficient mice. Nat Med 12:133–137

    Article  CAS  PubMed  Google Scholar 

  • Yao Y, Rabodzey A, Dewey CF Jr (2007) Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress. Am J Physiol Heart Circ Physiol 293:H1023–H1030

    Article  CAS  PubMed  Google Scholar 

  • Yeh JC, Otte LA, Frangos JA (2008) Regulation of g protein-coupled receptor activities by the platelet-endothelial cell adhesion molecule, pecam-1. Biochemistry 47:9029–9039

    Article  CAS  PubMed  Google Scholar 

  • Yu J, Bergaya S, Murata T, Alp IF, Bauer MP, Lin MI, Drab M, Kurzchalia TV, Stan RV, Sessa WC (2006) Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J Clin Invest 116:1284–1291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou J, Lee PL, Tsai CS, Lee CI, Yang TL, Chuang HS, Lin WW, Lin TE, Lim SH, Wei SY, Chen YL, Chien S, Chiu JJ (2012) Force-specific activation of smad1/5 regulates vascular endothelial cell cycle progression in response to disturbed flow. Proc Natl Acad Sci U S A 109:7770–7775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou J, Lee PL, Lee CI, Wei SY, Lim SH, Lin TE, Chien S, Chiu JJ (2013) Bmp receptor-integrin interaction mediates responses of vascular endothelial smad1/5 and proliferation to disturbed flow. J Thromb Haemost 11:741–755

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeng-Jiann Chiu Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2016 The American Physiological Society

About this chapter

Cite this chapter

Chen, LJ., Wang, WL., Chiu, JJ. (2016). Vascular Endothelial Mechanosensors in Response to Fluid Shear Stress. In: Chien, S., Engler, A., Wang, P. (eds) Molecular and Cellular Mechanobiology. Physiology in Health and Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-5617-3_2

Download citation

Publish with us

Policies and ethics