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TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension

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Abstract

The phenotypic modulation of contractile vascular smooth muscle cell (VSMC) is widely accepted as the pivotal process in the arterial remodeling induced by hypertension. This study aimed to investigate the potential role of transient receptor potential vanilloid type 1 (TRPV1) on regulating VSMC plasticity and intracranial arteriole remodeling in hypertension. Spontaneously hypertensive rats (SHR), Wistar–Kyoto (WKY) rats and TRPV1−/− mice on a C57BL/6J background were used. By microscopic observation of the histopathological sections of vessels from hypertensive SHR and age-matched normotensive WKY control rats, we found that hypertension induced arterial remodeling. Decreased α-smooth muscle actin (α-SMA) and SM22α while increased osteopontin (OPN) were observed in aorta and VSMCs derived from SHR compared with those in WKY, and VSMCs derived from SHR upregulated inflammatory factors. TRPV1 activation by capsaicin significantly increased expression of α-SMA and SM22α, reduced expression of OPN, retarded proliferative and migratory capacities and inhibited inflammatory status in VSMCs from SHR, which was counteracted by TRPV1 antagonist 5′-iodoresiniferatoxin (iRTX) combined with capsaicin. TRPV1 activation by capsaicin ameliorated intracranial arteriole remodeling in SHR and deoxycorticosterone acetate (DOCA)-salt hypertensive mice. However, the attenuation of arteriole remodeling by capsaicin was not observed in TRPV1−/− mice. Furthermore, TRPV1 activation significantly decreased the activity of PI3K and phosphorylation level of Akt in SHR-derived VSMCs. Taken together, we provide evidence that TRPV1 activation by capsaicin attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation during hypertension, which may be at least partly attributed to the suppression PI3K/Akt signaling pathway. These findings highlight the prospect of TRPV1 in prevention and treatment of hypertension.

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References

  • Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, Levine JD, Julius D (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389(6653):816–824. doi:10.1038/39807

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Zhang Z-F, Liao M-F, Yao W-L, Wang J, Wang X-R (2015) Blocking PAR2 attenuates oxaliplatin-induced neuropathic pain via TRPV1 and releases of substance P and CGRP in superficial dorsal horn of spinal cord. J Neurol Sci 352(1):62–67. doi:10.1016/j.jns.2015.03.029

    Article  CAS  PubMed  Google Scholar 

  • Doran AC, Meller N, McNamara CA (2008) Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol 28(5):812–819. doi:10.1161/ATVBAHA.107.159327

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fang D, Kong LY, Cai J, Li S, Liu XD, Han JS, Xing GG (2015) Interleukin-6-mediated functional upregulation of TRPV1 receptors in dorsal root ganglion neurons through the activation of JAK/PI3K signaling pathway: roles in the development of bone cancer pain in a rat model. Pain 156(6):1124–1144. doi:10.1097/j.pain.0000000000000158

    CAS  PubMed  Google Scholar 

  • Farb A, Kolodgie FD, Hwang JY, Burke AP, Tefera K, Weber DK, Wight TN, Virmani R (2004) Extracellular matrix changes in stented human coronary arteries. Circulation 110(8):940–947. doi:10.1161/01.CIR.0000139337.56084.30

    Article  CAS  PubMed  Google Scholar 

  • Fernandez-Hernando C, Jozsef L, Jenkins D, Di Lorenzo A, Sessa WC (2009) Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis. Arterioscler Thromb Vasc Biol 29(12):2033–2040. doi:10.1161/ATVBAHA.109.196394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franco-Cereceda A, Rudehill A (1989) Capsaicin-induced vasodilatation of human coronary arteries in vitro is mediated by calcitonin gene-related peptide rather than substance P or neurokinin A. Acta Physiol Scand 136(4):575–580. doi:10.1111/j.1748-1716.1989.tb08704.x

    Article  CAS  PubMed  Google Scholar 

  • Furgeson SB, Simpson PA, Park I, Vanputten V, Horita H, Kontos CD, Nemenoff RA, Weiser-Evans MC (2010) Inactivation of the tumour suppressor, PTEN, in smooth muscle promotes a pro-inflammatory phenotype and enhances neointima formation. Cardiovasc Res 86(2):274–282. doi:10.1093/cvr/cvp425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta S, Lozano-Cuenca J, Villalon CM, de Vries R, Garrelds IM, Avezaat CJ, van Kats JP, Saxena PR, MaassenVanDenBrink A (2007) Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries. Naunyn Schmiedeberg’s Arch Pharmacol 375(1):29–38. doi:10.1007/s00210-007-0137-y

    Article  CAS  Google Scholar 

  • Huang W, Rubinstein J, Prieto AR, Thang LV, Wang DH (2009) Transient receptor potential vanilloid gene deletion exacerbates inflammation and atypical cardiac remodeling after myocardial infarction. Hypertension 53(2):243–250. doi:10.1161/HYPERTENSIONAHA.108.118349

    Article  CAS  PubMed  Google Scholar 

  • Jayant S, Sharma BM, Sharma B (2016) Protective effect of transient receptor potential vanilloid subtype 1 (TRPV1) modulator, against behavioral, biochemical and structural damage in experimental models of Alzheimer’s disease. Brain Res 1642:397–408. doi:10.1016/j.brainres.2016.04.022

    Article  CAS  PubMed  Google Scholar 

  • Kang JH, Goto T, Han IS, Kawada T, Kim YM, Yu R (2010) Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity 18(4):780–787. doi:10.1038/oby.2009.301

    Article  CAS  PubMed  Google Scholar 

  • Kawasaki H, Takatori S, Zamami Y, Koyama T, Goda M, Hirai K, Tangsucharit P, Jin X, Hobara N, Kitamura Y (2011) Paracrine control of mesenteric perivascular axo-axonal interaction. Acta Physiol (Oxf) 203(1):3–11. doi:10.1111/j.1748-1716.2010.02197.x

    Article  CAS  Google Scholar 

  • Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK, He J (2005) Global burden of hypertension: analysis of worldwide data. Lancet 365(9455):217–223. doi:10.1016/s0140-6736(05)17741-1

    Article  PubMed  Google Scholar 

  • Kudryavtseva O, Herum KM, Dam VS, Straarup MS, Kamaev D, Briggs Boedtkjer DM, Matchkov VV, Aalkjær C (2014) Downregulation of L-type Ca2 + channel in rat mesenteric arteries leads to loss of smooth muscle contractile phenotype and inward hypertrophic remodeling. Am J Physiol Heart Circ Physiol 306(9):H1287–H1301

    Article  CAS  PubMed  Google Scholar 

  • Lee TH, Sottile J, Chiang HY (2015) Collagen inhibitory peptide R1R2 mediates vascular remodeling by decreasing inflammation and smooth muscle cell activation. PLoS ONE 10(2):e0117356. doi:10.1371/journal.pone.0117356

    Article  PubMed  PubMed Central  Google Scholar 

  • Levy D, Ehret GB, Rice K, Verwoert GC, Launer LJ, Dehghan A, Glazer NL, Morrison AC, Johnson AD, Aspelund T, Aulchenko Y, Lumley T, Kottgen A, Vasan RS, Rivadeneira F, Eiriksdottir G, Guo X, Arking DE, Mitchell GF, Mattace-Raso FU, Smith AV, Taylor K, Scharpf RB, Hwang SJ, Sijbrands EJ, Bis J, Harris TB, Ganesh SK, O’Donnell CJ, Hofman A, Rotter JI, Coresh J, Benjamin EJ, Uitterlinden AG, Heiss G, Fox CS, Witteman JC, Boerwinkle E, Wang TJ, Gudnason V, Larson MG, Chakravarti A, Psaty BM, van Duijn CM (2009) Genome-wide association study of blood pressure and hypertension. Nat Genet 41(6):677–687. doi:10.1038/ng.384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Wang DH (2003a) Function and regulation of the vanilloid receptor in rats fed a high salt diet. J Hypertens 21(8):1525–1530. doi:10.1097/01.hjh.0000084709.87421.98

    Article  CAS  PubMed  Google Scholar 

  • Li J, Wang DH (2003b) High-salt-induced increase in blood pressure: role of capsaicin-sensitive sensory nerves. J Hypertens 21(3):577–582. doi:10.1097/01.hjh.0000052465.40108.35

    Article  CAS  PubMed  Google Scholar 

  • Li BH, Yin YW, Liu Y, Pi Y, Guo L, Cao XJ, Gao CY, Zhang LL, Li JC (2014) TRPV1 activation impedes foam cell formation by inducing autophagy in oxLDL-treated vascular smooth muscle cells. Cell Death Dis 5:e1182. doi:10.1038/cddis.2014.146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ma L, Zhong J, Zhao Z, Luo Z, Ma S, Sun J, He H, Zhu T, Liu D, Zhu Z, Tepel M (2011) Activation of TRPV1 reduces vascular lipid accumulation and attenuates atherosclerosis. Cardiovasc Res 92(3):504–513. doi:10.1093/cvr/cvr245

    Article  CAS  PubMed  Google Scholar 

  • McMurray HF, Parrott DP, Bowyer DE (1991) A standardised method of culturing aortic explants, suitable for the study of factors affecting the phenotypic modulation, migration and proliferation of aortic smooth muscle cells. Atherosclerosis 86(2–3):227–237. doi:10.1016/0021-9150(91)90219-S

    Article  CAS  PubMed  Google Scholar 

  • Nam JH, Park ES, Won SY, Lee YA, Kim KI, Jeong JY, Baek JY, Cho EJ, Jin M, Chung YC, Lee BD, Kim SH, Kim EG, Byun K, Lee B, Woo DH, Lee CJ, Kim SR, Bok E, Kim YS, Ahn TB, Ko HW, Brahmachari S, Pletinkova O, Troconso JC, Dawson VL, Dawson TM, Jin BK (2015) TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF. Brain 138(Pt 12):3610–3622. doi:10.1093/brain/awv297

    Article  PubMed  PubMed Central  Google Scholar 

  • Owens GK, Kumar MS, Wamhoff BR (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84(3):767–801

    Article  CAS  PubMed  Google Scholar 

  • Pacher P, Batkai S, Kunos G (2004) Haemodynamic profile and responsiveness to anandamide of TRPV1 receptor knock-out mice. J Physiol 558(Pt 2):647–657. doi:10.1113/jphysiol.2004.064824

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palazzo E, Rossi F, Maione S (2008) Role of TRPV1 receptors in descending modulation of pain. Mol Cell Endocrinol 286(Suppl 1):S79–83. doi:10.1016/j.mce.2008.01.013

    PubMed  Google Scholar 

  • Perez-Rivera AA, Fink GD, Galligan JJ (2005) Vascular reactivity of mesenteric arteries and veins to endothelin-1 in a murine model of high blood pressure. Vascul Pharmacol 43(1):1–10. doi:10.1016/j.vph.2005.02.014

    Article  CAS  PubMed  Google Scholar 

  • Rayamajhi S, Contractor T, Wang DH (2009) The potential of TRPV1 agonists for treating ischemia/reperfusion-induced renal injuries. Curr Opin Investig Drugs 10(9):963–970

    CAS  PubMed  Google Scholar 

  • Scotland RS, Chauhan S, Davis C, De Felipe C, Hunt S, Kabir J, Kotsonis P, Oh U, Ahluwalia A (2004) Vanilloid receptor TRPV1, sensory C-fibers, and vascular autoregulation: a novel mechanism involved in myogenic constriction. Circ Res 95(10):1027–1034. doi:10.1161/01.RES.0000148633.93110.24

    Article  CAS  PubMed  Google Scholar 

  • Toth BI, Benko S, Szollosi AG, Kovacs L, Rajnavolgyi E, Biro T (2009) Transient receptor potential vanilloid-1 signaling inhibits differentiation and activation of human dendritic cells. FEBS Lett 583(10):1619–1624. doi:10.1016/j.febslet.2009.04.031

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Wang DH (2011) Protective effect of TRPV1 against renal fibrosis via inhibition of TGF-beta/Smad signaling in DOCA-salt hypertension. Mol Med 17(11–12):1204–1212. doi:10.2119/molmed.2011.00063

    PubMed  PubMed Central  Google Scholar 

  • Xu X, Wang P, Zhao Z, Cao T, He H, Luo Z, Zhong J, Gao F, Zhu Z, Li L, Yan Z, Chen J, Ni Y, Liu D, Zhu Z (2011) Activation of transient receptor potential vanilloid 1 by dietary capsaicin delays the onset of stroke in stroke-prone spontaneously hypertensive rats. Stroke 42(11):3245–3251. doi:10.1161/strokeaha.111.618306

    Article  CAS  PubMed  Google Scholar 

  • Yang D, Luo Z, Ma S, Wong WT, Ma L, Zhong J, He H, Zhao Z, Cao T, Yan Z, Liu D, Arendshorst WJ, Huang Y, Tepel M, Zhu Z (2010) Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension. Cell Metab 12(2):130–141. doi:10.1016/j.cmet.2010.05.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang LL, Liu DY, Ma LQ, Luo ZD, Cao TB, Zhong J, Yan ZC, Wang LJ, Zhao ZG, Zhu SJ, Schrader M, Thilo F, Zhu ZM, Tepel M (2007) Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res 100(7):1063–1070. doi:10.1161/01.RES.0000262653.84850.8b

    Article  CAS  PubMed  Google Scholar 

  • Zhang L, Xie P, Wang J, Yang Q, Fang C, Zhou S, Li J (2010) Impaired peroxisome proliferator-activated receptor-gamma contributes to phenotypic modulation of vascular smooth muscle cells during hypertension. J Biol Chem 285(18):13666–13677. doi:10.1074/jbc.M109.087718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang LL, Gao CY, Fang CQ, Wang YJ, Gao D, Yao GE, Xiang J, Wang JZ, Li JC (2011) PPARgamma attenuates intimal hyperplasia by inhibiting TLR4-mediated inflammation in vascular smooth muscle cells. Cardiovasc Res 92(3):484–493. doi:10.1093/cvr/cvr238

    Article  CAS  PubMed  Google Scholar 

  • Zhang M-J, Yin Y-W, Li B-H, Liu Y, Liao S-Q, Gao C-Y, Li J-C, Zhang L-L (2015) The role of TRPV1 in improving VSMC function and attenuating hypertension. Prog Biophys Mol Biol 117(2–3):212–216. doi:10.1016/j.pbiomolbio.2015.03.004

    Article  CAS  PubMed  Google Scholar 

  • Zhao Q, Zhang J, Wang H (2015) PGC-1α overexpression suppresses blood pressure elevation in DOCA-salt hypertensive mice. Biosci Rep 35(3):e00217. doi:10.1042/bsr20150076

    PubMed  PubMed Central  Google Scholar 

  • Zhong B, Wang DH (2007) TRPV1 gene knockout impairs preconditioning protection against myocardial injury in isolated perfused hearts in mice. Am J Physiol Heart Circ Physiol 293(3):H1791–1798. doi:10.1152/ajpheart.00169.2007

    Article  Google Scholar 

  • Zhong B, Wang DH (2008) N-oleoyldopamine, a novel endogenous capsaicin-like lipid, protects the heart against ischemia-reperfusion injury via activation of TRPV1. Am J Physiol Heart Circ Physiol 295(2):H728–735. doi:10.1152/ajpheart.00022.2008

    Article  Google Scholar 

  • Zhu Y, Colak T, Shenoy M, Liu L, Pai R, Li C, Mehta K, Pasricha PJ (2011) Nerve growth factor modulates TRPV1 expression and function and mediates pain in chronic pancreatitis. Gastroenterology 141(1):370–377. doi:10.1053/j.gastro.2011.03.046

    Article  CAS  PubMed  Google Scholar 

  • Zschenderlein C, Gebhardt C, und Halbach OVB, Kulisch C, Albrecht D (2011) Capsaicin-induced changes in LTP in the lateral amygdala are mediated by TRPV1. PLoS ONE 6(1):e16116. doi:10.1371/journal.pone.0016116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by Natural Science Foundation Project of CQ CSTC (CSTC2012JJJQ10003 to Li-Li Zhang) and National Natural Science Foundation of China (NSFC 81471193 to Li-Li Zhang, 81271282 to Jing-Cheng Li and 81400967 to Yan Pi).

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    Authors and Affiliations

    1. Department of Neurology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, No. 10 Changjiang Branch Road, Yuzhong District, Chongqing, 400042, People’s Republic of China

      Ming-Jie Zhang, Yun Liu, Zi-Cheng Hu, Yi Zhou, Yan Pi, Lu Guo, Xu Wang, Xue Chen, Jing-Cheng Li & Li-Li Zhang

    2. Department of Neurology, Chengdu Military General Hospital, No. 270 Rongdu Avenue, Jinniu District, Chengdu, 610083, Sichuan Province, People’s Republic of China

      Ming-Jie Zhang

    3. Department of Neurology, No. 97 Hospital of PLA, No. 226 Tongshan Road, Yunlong District, Xuzhou, 221004, Jiangsu Province, People’s Republic of China

      Yun Liu

    4. Department of Neurology, Bethune International Peace Hospital, No. 398 Zhongshan Road, Qiaoxi District, Shijiazhuang, 050082, Hebei Province, People’s Republic of China

      Yi Zhou

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    1. Ming-Jie Zhang
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    M.-J. Zhang and Y. Liu have contributed equally to this article.

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    Zhang, MJ., Liu, Y., Hu, ZC. et al. TRPV1 attenuates intracranial arteriole remodeling through inhibiting VSMC phenotypic modulation in hypertension. Histochem Cell Biol 147, 511–521 (2017). https://doi.org/10.1007/s00418-016-1512-x

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