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• W2171517688 abstract "•Smooth muscle Piezo1 is required for stretch-activated cationic channel activity•Piezo1 is dispensable for the arterial myogenic tone•Piezo1 opening has a trophic effect on the arterial wall of small arteries•Piezo1 activation increases cytosolic calcium and transglutaminase activity The mechanically activated non-selective cation channel Piezo1 is a determinant of vascular architecture during early development. Piezo1-deficient embryos die at midgestation with disorganized blood vessels. However, the role of stretch-activated ion channels (SACs) in arterial smooth muscle cells in the adult remains unknown. Here, we show that Piezo1 is highly expressed in myocytes of small-diameter arteries and that smooth-muscle-specific Piezo1 deletion fully impairs SAC activity. While Piezo1 is dispensable for the arterial myogenic tone, it is involved in the structural remodeling of small arteries. Increased Piezo1 opening has a trophic effect on resistance arteries, influencing both diameter and wall thickness in hypertension. Piezo1 mediates a rise in cytosolic calcium and stimulates activity of transglutaminases, cross-linking enzymes required for the remodeling of small arteries. In conclusion, we have established the connection between an early mechanosensitive process, involving Piezo1 in smooth muscle cells, and a clinically relevant arterial remodeling. The mechanically activated non-selective cation channel Piezo1 is a determinant of vascular architecture during early development. Piezo1-deficient embryos die at midgestation with disorganized blood vessels. However, the role of stretch-activated ion channels (SACs) in arterial smooth muscle cells in the adult remains unknown. Here, we show that Piezo1 is highly expressed in myocytes of small-diameter arteries and that smooth-muscle-specific Piezo1 deletion fully impairs SAC activity. While Piezo1 is dispensable for the arterial myogenic tone, it is involved in the structural remodeling of small arteries. Increased Piezo1 opening has a trophic effect on resistance arteries, influencing both diameter and wall thickness in hypertension. Piezo1 mediates a rise in cytosolic calcium and stimulates activity of transglutaminases, cross-linking enzymes required for the remodeling of small arteries. In conclusion, we have established the connection between an early mechanosensitive process, involving Piezo1 in smooth muscle cells, and a clinically relevant arterial remodeling. The molecular identity of non-selective stretch-activated ion channels (SACs) has long remained a mystery (Nilius, 2010Nilius B. Pressing and squeezing with Piezos.EMBO Rep. 2010; 11: 902-903Crossref PubMed Scopus (22) Google Scholar, Pedersen and Nilius, 2007Pedersen S.F. Nilius B. Transient receptor potential channels in mechanosensing and cell volume regulation.Methods Enzymol. 2007; 428: 183-207Crossref PubMed Scopus (110) Google Scholar). Only recently, Piezo1 and Piezo2 were shown to be essential components of distinct SACs (Coste et al., 2010Coste B. Mathur J. Schmidt M. Earley T.J. Ranade S. Petrus M.J. Dubin A.E. Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.Science. 2010; 330: 55-60Crossref PubMed Scopus (1525) Google Scholar). Piezo1 is a pore-forming subunit, as demonstrated by functional reconstitution into artificial bilayers (Coste et al., 2012Coste B. Xiao B. Santos J.S. Syeda R. Grandl J. Spencer K.S. Kim S.E. Schmidt M. Mathur J. Dubin A.E. et al.Piezo proteins are pore-forming subunits of mechanically activated channels.Nature. 2012; 483: 176-181Crossref PubMed Scopus (646) Google Scholar). Piezo1 exogenous depolarizing currents can be activated in the whole cell configuration upon pressure stimulation with a glass stylus, by fluid flow, by substrate deflection, or in the cell-attached patch configuration by applying a negative pressure (Bae et al., 2011Bae C. Sachs F. Gottlieb P.A. The mechanosensitive ion channel Piezo1 is inhibited by the peptide GsMTx4.Biochemistry. 2011; 50: 6295-6300Crossref PubMed Scopus (275) Google Scholar, Coste et al., 2010Coste B. Mathur J. Schmidt M. Earley T.J. Ranade S. Petrus M.J. Dubin A.E. Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.Science. 2010; 330: 55-60Crossref PubMed Scopus (1525) Google Scholar, Gottlieb et al., 2012Gottlieb P.A. Bae C. Sachs F. Gating the mechanical channel Piezo1: a comparison between whole-cell and patch recording.Channels (Austin). 2012; 6: 282-289Crossref PubMed Scopus (130) Google Scholar, Li et al., 2014Li J. Hou B. Tumova S. Muraki K. Bruns A. Ludlow M.J. Sedo A. Hyman A.J. McKeown L. Young R.S. et al.Piezo1 integration of vascular architecture with physiological force.Nature. 2014; 515: 279-282Crossref PubMed Scopus (607) Google Scholar, Peyronnet et al., 2013Peyronnet R. Martins J.R. Duprat F. Demolombe S. Arhatte M. Jodar M. Tauc M. Duranton C. Paulais M. Teulon J. et al.Piezo1-dependent stretch-activated channels are inhibited by Polycystin-2 in renal tubular epithelial cells.EMBO Rep. 2013; 14: 1143-1148Crossref PubMed Scopus (93) Google Scholar, Poole et al., 2014Poole K. Herget R. Lapatsina L. Ngo H.D. Lewin G.R. Tuning Piezo ion channels to detect molecular-scale movements relevant for fine touch.Nat. Commun. 2014; 5: 3520Crossref PubMed Scopus (167) Google Scholar, Ranade et al., 2014Ranade S.S. Qiu Z. Woo S.H. Hur S.S. Murthy S.E. Cahalan S.M. Xu J. Mathur J. Bandell M. Coste B. et al.Piezo1, a mechanically activated ion channel, is required for vascular development in mice.Proc. Natl. Acad. Sci. USA. 2014; 111: 10347-10352Crossref PubMed Scopus (483) Google Scholar). In terms of permeability, Na+, K+, Ca2+, and Mg2+ all permeate the channel, with a slight preference for Ca2+ (Coste et al., 2010Coste B. Mathur J. Schmidt M. Earley T.J. Ranade S. Petrus M.J. Dubin A.E. Patapoutian A. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels.Science. 2010; 330: 55-60Crossref PubMed Scopus (1525) Google Scholar). Global knockout of Piezo1 is embryonically lethal, thus indicating an important role for this mechanosensitive ion channel in early development (Li et al., 2014Li J. Hou B. Tumova S. Muraki K. Bruns A. Ludlow M.J. Sedo A. Hyman A.J. McKeown L. Young R.S. et al.Piezo1 integration of vascular architecture with physiological force.Nature. 2014; 515: 279-282Crossref PubMed Scopus (607) Google Scholar, Ranade et al., 2014Ranade S.S. Qiu Z. Woo S.H. Hur S.S. Murthy S.E. Cahalan S.M. Xu J. Mathur J. Bandell M. Coste B. et al.Piezo1, a mechanically activated ion channel, is required for vascular development in mice.Proc. Natl. Acad. Sci. USA. 2014; 111: 10347-10352Crossref PubMed Scopus (483) Google Scholar). Piezo1 is expressed in the endothelium of developing blood vessels, and its genetic deletion profoundly alters vascular architecture (Li et al., 2014Li J. Hou B. Tumova S. Muraki K. Bruns A. Ludlow M.J. Sedo A. Hyman A.J. McKeown L. Young R.S. et al.Piezo1 integration of vascular architecture with physiological force.Nature. 2014; 515: 279-282Crossref PubMed Scopus (607) Google Scholar, Ranade et al., 2014Ranade S.S. Qiu Z. Woo S.H. Hur S.S. Murthy S.E. Cahalan S.M. Xu J. Mathur J. Bandell M. Coste B. et al.Piezo1, a mechanically activated ion channel, is required for vascular development in mice.Proc. Natl. Acad. Sci. USA. 2014; 111: 10347-10352Crossref PubMed Scopus (483) Google Scholar). Piezo1 expression in the endothelium confers sensitivity to shear stress, resulting in a calcium influx in response to increased fluid flow (Li et al., 2014Li J. Hou B. Tumova S. Muraki K. Bruns A. Ludlow M.J. Sedo A. Hyman A.J. McKeown L. Young R.S. et al.Piezo1 integration of vascular architecture with physiological force.Nature. 2014; 515: 279-282Crossref PubMed Scopus (607) Google Scholar, Ranade et al., 2014Ranade S.S. Qiu Z. Woo S.H. Hur S.S. Murthy S.E. Cahalan S.M. Xu J. Mathur J. Bandell M. Coste B. et al.Piezo1, a mechanically activated ion channel, is required for vascular development in mice.Proc. Natl. Acad. Sci. USA. 2014; 111: 10347-10352Crossref PubMed Scopus (483) Google Scholar). Loss of Piezo1 in endothelial cells leads to altered stress fiber organization and cell orientation in response to shear stress (Li et al., 2014Li J. Hou B. Tumova S. Muraki K. Bruns A. Ludlow M.J. Sedo A. Hyman A.J. McKeown L. Young R.S. et al.Piezo1 integration of vascular architecture with physiological force.Nature. 2014; 515: 279-282Crossref PubMed Scopus (607) Google Scholar, Ranade et al., 2014Ranade S.S. Qiu Z. Woo S.H. Hur S.S. Murthy S.E. Cahalan S.M. Xu J. Mathur J. Bandell M. Coste B. et al.Piezo1, a mechanically activated ion channel, is required for vascular development in mice.Proc. Natl. Acad. Sci. USA. 2014; 111: 10347-10352Crossref PubMed Scopus (483) Google Scholar). These elegant findings indicate that shear stress activation of endothelial Piezo1 is required for the proper development of blood vessels (Li et al., 2014Li J. Hou B. Tumova S. Muraki K. Bruns A. Ludlow M.J. Sedo A. Hyman A.J. McKeown L. Young R.S. et al.Piezo1 integration of vascular architecture with physiological force.Nature. 2014; 515: 279-282Crossref PubMed Scopus (607) Google Scholar, Ranade et al., 2014Ranade S.S. Qiu Z. Woo S.H. Hur S.S. Murthy S.E. Cahalan S.M. Xu J. Mathur J. Bandell M. Coste B. et al.Piezo1, a mechanically activated ion channel, is required for vascular development in mice.Proc. Natl. Acad. Sci. USA. 2014; 111: 10347-10352Crossref PubMed Scopus (483) Google Scholar). The opening of SACs at the plasma membrane of smooth muscle cells has been proposed as a triggering mechanism for the myogenic response (Beech, 2005Beech D.J. Emerging functions of 10 types of TRP cationic channel in vascular smooth muscle.Clin. Exp. Pharmacol. Physiol. 2005; 32: 597-603Crossref PubMed Scopus (89) Google Scholar, Brayden et al., 2008Brayden J.E. Earley S. Nelson M.T. Reading S. Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow.Clin. Exp. Pharmacol. Physiol. 2008; 35: 1116-1120Crossref PubMed Scopus (103) Google Scholar, Davis and Hill, 1999Davis M.J. Hill M.A. Signaling mechanisms underlying the vascular myogenic response.Physiol. Rev. 1999; 79: 387-423Crossref PubMed Scopus (819) Google Scholar, Folgering et al., 2008Folgering J.H. Sharif-Naeini R. Dedman A. Patel A. Delmas P. Honoré E. Molecular basis of the mammalian pressure-sensitive ion channels: focus on vascular mechanotransduction.Prog. Biophys. Mol. Biol. 2008; 97: 180-195Crossref PubMed Scopus (54) Google Scholar, Hill et al., 2006Hill M.A. Davis M.J. Meininger G.A. Potocnik S.J. Murphy T.V. Arteriolar myogenic signalling mechanisms: Implications for local vascular function.Clin. Hemorheol. Microcirc. 2006; 34: 67-79PubMed Google Scholar). The myogenic response is a tonic vasoconstriction of small-diameter arteries in response to an increase in intraluminal pressure and serves to maintain a constant blood flow within a wide range of blood pressures and is required for the establishment of a basal tone upon which vasorelaxing agents may act (Davis and Hill, 1999Davis M.J. Hill M.A. Signaling mechanisms underlying the vascular myogenic response.Physiol. Rev. 1999; 79: 387-423Crossref PubMed Scopus (819) Google Scholar, Hill et al., 2006Hill M.A. Davis M.J. Meininger G.A. Potocnik S.J. Murphy T.V. Arteriolar myogenic signalling mechanisms: Implications for local vascular function.Clin. Hemorheol. Microcirc. 2006; 34: 67-79PubMed Google Scholar). While, various inhibitors of SACs have been shown to significantly reduce the amplitude of the myogenic response in different vascular beds (Drummond et al., 2004Drummond H.A. Gebremedhin D. Harder D.R. Degenerin/epithelial Na+ channel proteins: components of a vascular mechanosensor.Hypertension. 2004; 44: 643-648Crossref PubMed Scopus (146) Google Scholar, Earley et al., 2004Earley S. Waldron B.J. Brayden J.E. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries.Circ. Res. 2004; 95: 922-929Crossref PubMed Scopus (308) Google Scholar, Jernigan and Drummond, 2006Jernigan N.L. Drummond H.A. Myogenic vasoconstriction in mouse renal interlobar arteries: role of endogenous beta and gammaENaC.Am. J. Physiol. Renal Physiol. 2006; 291: F1184-F1191Crossref PubMed Scopus (90) Google Scholar, Takenaka et al., 1998aTakenaka T. Suzuki H. Okada H. Hayashi K. Kanno Y. Saruta T. Mechanosensitive cation channels mediate afferent arteriolar myogenic constriction in the isolated rat kidney.J. Physiol. 1998; 511: 245-253Crossref PubMed Scopus (42) Google Scholar, Takenaka et al., 1998bTakenaka T. Suzuki H. Okada H. Hayashi K. Ozawa Y. Saruta T. Biophysical signals underlying myogenic responses in rat interlobular artery.Hypertension. 1998; 32: 1060-1065Crossref PubMed Scopus (22) Google Scholar, Welsh et al., 2002Welsh D.G. Morielli A.D. Nelson M.T. Brayden J.E. Transient receptor potential channels regulate myogenic tone of resistance arteries.Circ. Res. 2002; 90: 248-250Crossref PubMed Scopus (430) Google Scholar), non-specific effects of these pharmacological agents cannot be entirely ruled out. Moreover, the molecular identity of SACs in arterial myocytes remains obscure, with a possible involvement of epithelial Na+ channel (ENaC) and/or transient receptor potential (TRP) subunits (Drummond et al., 2004Drummond H.A. Gebremedhin D. Harder D.R. Degenerin/epithelial Na+ channel proteins: components of a vascular mechanosensor.Hypertension. 2004; 44: 643-648Crossref PubMed Scopus (146) Google Scholar, Earley et al., 2004Earley S. Waldron B.J. Brayden J.E. Critical role for transient receptor potential channel TRPM4 in myogenic constriction of cerebral arteries.Circ. Res. 2004; 95: 922-929Crossref PubMed Scopus (308) Google Scholar, Jernigan and Drummond, 2006Jernigan N.L. Drummond H.A. Myogenic vasoconstriction in mouse renal interlobar arteries: role of endogenous beta and gammaENaC.Am. J. Physiol. Renal Physiol. 2006; 291: F1184-F1191Crossref PubMed Scopus (90) Google Scholar, Lee et al., 2007Lee H.A. Baek E.B. Park K.S. Jung H.J. Kim J.I. Kim S.J. Earm Y.E. Mechanosensitive nonselective cation channel facilitation by endothelin-1 is regulated by protein kinase C in arterial myocytes.Cardiovasc. Res. 2007; 76: 224-235Crossref PubMed Scopus (23) Google Scholar, Park et al., 2003Park K.S. Kim Y. Lee Y.H. Earm Y.E. Ho W.K. Mechanosensitive cation channels in arterial smooth muscle cells are activated by diacylglycerol and inhibited by phospholipase C inhibitor.Circ. Res. 2003; 93: 557-564Crossref PubMed Scopus (55) Google Scholar, Takenaka et al., 1998aTakenaka T. Suzuki H. Okada H. Hayashi K. Kanno Y. Saruta T. Mechanosensitive cation channels mediate afferent arteriolar myogenic constriction in the isolated rat kidney.J. Physiol. 1998; 511: 245-253Crossref PubMed Scopus (42) Google Scholar, Takenaka et al., 1998bTakenaka T. Suzuki H. Okada H. Hayashi K. Ozawa Y. Saruta T. Biophysical signals underlying myogenic responses in rat interlobular artery.Hypertension. 1998; 32: 1060-1065Crossref PubMed Scopus (22) Google Scholar, Welsh et al., 2002Welsh D.G. Morielli A.D. Nelson M.T. Brayden J.E. Transient receptor potential channels regulate myogenic tone of resistance arteries.Circ. Res. 2002; 90: 248-250Crossref PubMed Scopus (430) Google Scholar). In addition to an acute myogenic regulation of arterial diameter, resistance arteries also have the ability to regulate their caliber during chronic hypertension by a phenomenon called arterial remodeling, operating on a timescale of several days (Bakker et al., 2005Bakker E.N. Buus C.L. Spaan J.A. Perree J. Ganga A. Rolf T.M. Sorop O. Bramsen L.H. Mulvany M.J. Vanbavel E. Small artery remodeling depends on tissue-type transglutaminase.Circ. Res. 2005; 96: 119-126Crossref PubMed Scopus (150) Google Scholar, Bakker et al., 2008Bakker E.N. Pistea A. VanBavel E. Transglutaminases in vascular biology: relevance for vascular remodeling and atherosclerosis.J. Vasc. Res. 2008; 45: 271-278Crossref PubMed Scopus (73) Google Scholar, Martinez-Lemus et al., 2009Martinez-Lemus L.A. Hill M.A. Meininger G.A. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure.Physiology (Bethesda). 2009; 24: 45-57Crossref PubMed Scopus (191) Google Scholar, Mulvany, 2002Mulvany M.J. Small artery remodeling and significance in the development of hypertension.News Physiol. Sci. 2002; 17: 105-109PubMed Google Scholar). Arterial remodeling is a structural adaptation of the vessel wall to hemodynamic stimuli (Bakker et al., 2005Bakker E.N. Buus C.L. Spaan J.A. Perree J. Ganga A. Rolf T.M. Sorop O. Bramsen L.H. Mulvany M.J. Vanbavel E. Small artery remodeling depends on tissue-type transglutaminase.Circ. Res. 2005; 96: 119-126Crossref PubMed Scopus (150) Google Scholar, Bakker et al., 2008Bakker E.N. Pistea A. VanBavel E. Transglutaminases in vascular biology: relevance for vascular remodeling and atherosclerosis.J. Vasc. Res. 2008; 45: 271-278Crossref PubMed Scopus (73) Google Scholar, Martinez-Lemus et al., 2009Martinez-Lemus L.A. Hill M.A. Meininger G.A. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure.Physiology (Bethesda). 2009; 24: 45-57Crossref PubMed Scopus (191) Google Scholar, Mulvany, 2002Mulvany M.J. Small artery remodeling and significance in the development of hypertension.News Physiol. Sci. 2002; 17: 105-109PubMed Google Scholar). In chronic hypertension, conduit arteries undergo an hypertrophic remodeling, while resistance arteries show inward eutrophic remodeling, with a repositioning of smooth muscle cells around a smaller lumen diameter in the absence of hypertrophy (Mulvany, 2002Mulvany M.J. Small artery remodeling and significance in the development of hypertension.News Physiol. Sci. 2002; 17: 105-109PubMed Google Scholar). Those changes in wall thickness and diameter contribute, according to the law of Laplace (σ = Pri/h, where σ = wall stress, P = pressure, ri = inner arterial radius, and h = wall thickness), to the arterial wall tensional homeostasis (Khavandi et al., 2009Khavandi K. Greenstein A.S. Sonoyama K. Withers S. Price A. Malik R.A. Heagerty A.M. Myogenic tone and small artery remodelling: insight into diabetic nephropathy.Nephrol. Dial. Transplant. 2009; 24: 361-369Crossref PubMed Scopus (33) Google Scholar, Mulvany, 2002Mulvany M.J. Small artery remodeling and significance in the development of hypertension.News Physiol. Sci. 2002; 17: 105-109PubMed Google Scholar). Importantly, remodeling of small arteries has been linked to cardiovascular morbidity and mortality (Mathiassen et al., 2007Mathiassen O.N. Buus N.H. Sihm I. Thybo N.K. Mørn B. Schroeder A.P. Thygesen K. Aalkjaer C. Lederballe O. Mulvany M.J. Christensen K.L. Small artery structure is an independent predictor of cardiovascular events in essential hypertension.J. Hypertens. 2007; 25: 1021-1026Crossref PubMed Scopus (153) Google Scholar, Rizzoni et al., 2003Rizzoni D. Porteri E. Boari G.E. De Ciuceis C. Sleiman I. Muiesan M.L. Castellano M. Miclini M. Agabiti-Rosei E. Prognostic significance of small-artery structure in hypertension.Circulation. 2003; 108: 2230-2235Crossref PubMed Scopus (409) Google Scholar). Disorders in the structure and function of resistance arteries raise capillary pressure and may cause downstream organ damage, as occurring in diabetic nephropathy (Khavandi et al., 2009Khavandi K. Greenstein A.S. Sonoyama K. Withers S. Price A. Malik R.A. Heagerty A.M. Myogenic tone and small artery remodelling: insight into diabetic nephropathy.Nephrol. Dial. Transplant. 2009; 24: 361-369Crossref PubMed Scopus (33) Google Scholar). The molecular mechanisms implicated in the remodeling of resistance arteries during hypertension are only starting to emerge (Bakker et al., 2005Bakker E.N. Buus C.L. Spaan J.A. Perree J. Ganga A. Rolf T.M. Sorop O. Bramsen L.H. Mulvany M.J. Vanbavel E. Small artery remodeling depends on tissue-type transglutaminase.Circ. Res. 2005; 96: 119-126Crossref PubMed Scopus (150) Google Scholar, Bakker et al., 2008Bakker E.N. Pistea A. VanBavel E. Transglutaminases in vascular biology: relevance for vascular remodeling and atherosclerosis.J. Vasc. Res. 2008; 45: 271-278Crossref PubMed Scopus (73) Google Scholar, Martinez-Lemus et al., 2009Martinez-Lemus L.A. Hill M.A. Meininger G.A. The plastic nature of the vascular wall: a continuum of remodeling events contributing to control of arteriolar diameter and structure.Physiology (Bethesda). 2009; 24: 45-57Crossref PubMed Scopus (191) Google Scholar, Mulvany, 2002Mulvany M.J. Small artery remodeling and significance in the development of hypertension.News Physiol. Sci. 2002; 17: 105-109PubMed Google Scholar). Recent findings indicate that activation of the crosslinking enzyme transglutaminase 2 is involved in the remodeling of small arteries in hypertensive conditions (Bakker et al., 2005Bakker E.N. Buus C.L. Spaan J.A. Perree J. Ganga A. Rolf T.M. Sorop O. Bramsen L.H. Mulvany M.J. Vanbavel E. Small artery remodeling depends on tissue-type transglutaminase.Circ. Res. 2005; 96: 119-126Crossref PubMed Scopus (150) Google Scholar, Engholm et al., 2011Engholm M. Eftekhari A. Chwatko G. Bald E. Mulvany M.J. Effect of cystamine on blood pressure and vascular characteristics in spontaneously hypertensive rats.J. Vasc. Res. 2011; 48: 476-484Crossref PubMed Scopus (18) Google Scholar, Huelsz-Prince et al., 2013Huelsz-Prince G. Belkin A.M. VanBavel E. Bakker E.N. Activation of extracellular transglutaminase 2 by mechanical force in the arterial wall.J. Vasc. Res. 2013; 50: 383-395Crossref PubMed Scopus (29) Google Scholar). Here, using a combination of smooth-muscle-specific knockout mouse models, we explored the functional role of Piezo1 in the adult circulation. We show that, while Piezo1 is dispensable for the arterial myogenic tone, it is centrally involved in the remodeling of small arteries. qPCR analysis revealed that Piezo1, unlike Piezo2, is highly expressed in the cutaneous caudal artery (Figure 1A). We used the sm22Cre recombinase to specifically delete Piezo1 in smooth muscle cells of C57BL/6 male mice (sm22Cre Piezo1−/−) (Figures S1A–S1F). We observed a robust knockdown of Piezo1 in the caudal artery without compensation by Piezo2 expression (Figure 1A). Mouse weight, tibial length, and viability were not affected by specific deletion of Piezo1 in smooth muscle cells (Figures S1G and S1H). Moreover, arterial pressure was not significantly modified in the absence of Piezo1, in awake or anesthetized mice (Figures S1K–S1M). Taking advantage of a LacΖ Piezo1 reporter mouse, we observed a remarkably strong expression of Piezo1 (shown in blue) in the media of small-diameter arteries, with the strongest signals seen in the cutaneous caudal artery and cerebral arteries (Figures 1B–1D). Indeed, isolated smooth muscle cells from the caudal resistance artery were strongly positive for Piezo1, as visualized by intense LacΖ blue staining (Figures S1E and S1F). In contrast, a very low expression was detected in large-diameter conduit arteries, including the aorta or the main renal artery (Figures 1B and 1E). These findings indicate that Piezo1 is present at the adult stage in the smooth muscle of small arteries that participate actively in the regulation of peripheral resistance, as well as in the cerebral circulation. Moreover, Piezo1 in myocytes of small-diameter arteries is dramatically knocked down in the sm22Cre Piezo1−/− mouse model. We measured the activity of non-selective SACs in freshly isolated myocytes from the caudal artery using cell-attached patch clamp recordings (Figure 2A). SACs only partially inactivated during a maintained pressure pulse, and they reversed at about 0 mV, and the single-channel conductance was estimated to be about 35 pS (Figures 2A and 2B; Figure S2B). In line with the differential LacZ expression profile of Piezo1, SAC activity was significantly higher in smooth muscle cells derived from the caudal artery (128/187 active patches for sm22Cre Piezo1+/+) compared to that elicited in myocytes from the aorta (1/18) or renal arteries (7/34) (Figure 2C). Most importantly, SAC activity in caudal artery myocytes was dramatically reduced upon homozygote deletion of Piezo1 (9/114 active patches for sm22Cre Piezo1−/−; Figures 2C and S2A). These findings demonstrate that Piezo1 is critically required for non-selective SAC activity in smooth muscle cells of the caudal artery. One possible mechanism for initiation of the myogenic tone is the opening of SACs in arterial smooth muscle cells in response to an increase in wall tension (for reviews, see Davis and Hill, 1999Davis M.J. Hill M.A. Signaling mechanisms underlying the vascular myogenic response.Physiol. Rev. 1999; 79: 387-423Crossref PubMed Scopus (819) Google Scholar, Hill et al., 2006Hill M.A. Davis M.J. Meininger G.A. Potocnik S.J. Murphy T.V. Arteriolar myogenic signalling mechanisms: Implications for local vascular function.Clin. Hemorheol. Microcirc. 2006; 34: 67-79PubMed Google Scholar). Thus, we investigated whether Piezo1 knockout might influence the caudal artery myogenic tone. Pressure-dependent vasomotion was consistently present on top of the myogenic response in stop-flow experiments (Figure S3A). Myogenic response and vasomotion were also present when intraluminal flow was set at 15 μl/min, thus ruling out the possible contribution of an accumulating diffusible factor in the lumen (n = 3; data not shown). Moreover, myogenic response and vasomotion were observed in de-endothelized caudal arteries, while vasodilation induced by acetylcholine was lost (n = 3; not shown). The myogenic response reached a plateau at a pressure value of 50 mm Hg and further decreased in amplitude at pressure above 125 mm Hg (Figure S3B). The mean amplitude of vasomotion presented a maximum at 25 mm Hg and then gradually decreased at higher pressure values (Figure S3C). Remarkably, no significant change was observed upon Piezo1 knockout on either the myogenic response or pressure-dependent vasomotion (Figures S3B and S3C). Furthermore, the passive diameter measured in the absence of extracellular calcium and in the presence of vasorelaxants was unaffected in the absence of Piezo1 (Figure S3D). In addition, reactivity of the caudal artery to agonists—either vasoconstrictors or the vasorelaxant acetylcholine—as well as vasoconstriction induced by KCl (80 mM), was unaffected upon Piezo1 deletion (Figures S3E–S3I). These results indicate that Piezo1-dependent SAC activity is not required for the myogenic tone and reactivity to agonists of the cutaneous caudal artery. The lack of effect of Piezo1 knockout on the myogenic tone was confirmed with the rostral cerebellar artery, another vascular bed characterized by a high Piezo1 expression (Figure 1D). Again, SAC activity was absent (0/23 for sm22Cre Piezo1−/−, as compared to 10/12 for sm22Cre Piezo1+/+) in the isolated rostral cerebellar artery myocytes from sm22Cre Piezo1−/− mice, although myogenic response was unaffected (Figures S4A–S4C). Moreover, the passive arterial diameter of the rostral cerebellar artery was not modified in the absence of Piezo1 (Figure S4D). Thus, Piezo1 is dispensable for the active myogenic tone of both caudal and cerebral arteries. Moreover, the lack of Piezo1 does not alter basal passive arterial diameter (i.e., in the absence of extracellular calcium). Next, we tested whether the influence of Piezo1 on arterial dimensions might be revealed at higher blood pressure. We investigated whether the opening of Piezo1 in smooth muscle cells might influence caudal artery remodeling upon hypertension. We used an in vivo experimental model of chronic hypertension involving angiotensin II (Ang II) infusion (Figures S1G and S1H; Figures S1L and S1M). Arterial segments in the absence of extracellular calcium and in the presence of the vasorelaxant agents sodium nitroprusside and papaverine (i.e., without active tone) were fixed at 75 mm Hg for morphological examination (Figure 3). In normotensive control conditions (saline), homozygote smooth muscle Piezo1 deletion did not significantly affect caudal artery morphology, in line with our previous measurements of passive diameter by arteriography (Figure 3; Figure S3D). However, Piezo1 knockout in Ang-II-infused hypertensive mice resulted in a significant reduction in arterial diameter; wall thickness; and, consequently, cross-sectional area (CSA) (Figure 3). We used a second in vivo model of hypertension, involving deoxycorticosterone acetate (DOCA)/salt/uninephrectomy (Figures S1G and S1H; Figures S1L and S1M). In the DOCA/salt/uninephrectomy hypertension model, arterial dimensions were unaffected in control animals, despite a strong hypertensive effect (Figures 3E–3G; Figures S1L and S1M). However, again, both diameter and wall thickness dramatically decreased, resulting in a significant drop in CSA during DOCA/salt/uninephrectomy hypertension in the absence of smooth muscle Piezo1 (Figures 3E–3G). By labeling smooth muscle cells with an antibody directed against sm22, we confirmed that media thickness was reduced upon smPiezo1 deletion in the DOCA/salt/uninephrectomy hypertension model, although the endothelial cell layer was not visibly altered (Figures S5A and S5B). Using Hoechst staining, we further estimated, by confocal microscopy in thin sections, the number of nuclei present in the media (Figures S5A and S5C). In the DOCA/salt/uninephrectomy smPiezo1−/− mice, the number of nuclei was significantly decreased (Figure S5C). However, TUNEL staining, as well as Ki67 immunolocalization were both negative after 3 weeks of DOCA/salt/uninephrectomy hypertension in both smPiezo" @default.
• W2171517688 created "2016-06-24" @default.
• W2171517688 creator A5003450108 @default.
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• W2171517688 date "2015-11-01" @default.
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• W2171517688 title "Piezo1 in Smooth Muscle Cells Is Involved in Hypertension-Dependent Arterial Remodeling" @default.
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• W2171517688 doi "https://doi.org/10.1016/j.celrep.2015.09.072" @default.
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