Issue

Vol. 64 No. 7: Issue 7

The undersigned hereby assign all rights, included but not limited to copyright, for this manuscript to CMB Association upon its submission for consideration to publication on Cellular and Molecular Biology. The rights assigned include, but are not limited to, the sole and exclusive rights to license, sell, subsequently assign, derive, distribute, display and reproduce this manuscript, in whole or in part, in any format, electronic or otherwise, including those in existence at the time this agreement was signed. The authors hereby warrant that they have not granted or assigned, and shall not grant or assign, the aforementioned rights to any other person, firm, organization, or other entity. All rights are automatically restored to authors if this manuscript is not accepted for publication.

Cyclic stretch induces VEGFA alternative splicing via Serine/Arginine-Rich Splicing Factor 1

https://doi.org/10.14715/cmb/2018.64.7.8
Zhi-Wei Xie
Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Yuan-Xiu Chen
Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Cai-Feng Long
Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Ying-Xin Qi
Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Qing-Ping Yao
Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China

Corresponding Author(s) : Qing-Ping Yao

qpyao@sjtu.edu.cn

Cellular and Molecular Biology, Vol. 64 No. 7: Issue 7

Abstract

Abnormal proliferation of vascular smooth muscle cells (VSMCs) induced by high cyclic stretch is crucial in the vascular remodeling during hypertension. Vascular endothelial growth factor A (VEGFA) alternative splicing plays important roles in the pathological process of vascular diseases and remodeling. However, the roles of VEGFA isoforms in modulating VSMC functions in response to cyclic stretch remain unclear. We hypothesize that high cyclic stretch may induce VEGFA alternative splicing via Serine/arginine-rich splicing factor 1 (SRSF1) which subsequently induce VSMC proliferation. In the present research, hypertensive rat model was established using the abdominal aortic constriction method. In comparison with sham-operated group, immunohistology staining showed translocation of SRSF1 into nuclei in hypertensive rat thoracic aorta, and RT-PCR detected a shift of VEGFA expression pattern, including the increased expression of VEGFA120 and VEGFA164, but not VEGFA188.Then VSMCs were subjected to cyclic stretch in vitro using a Flexercell strain unit. VEGFA ELISA assay showed 15% cyclic stretch increased the secretion of VEGFA which significantly increased proliferation of VSMCs. Western blot and immunofluorescence detected accumulation of SRSF1 in nuclei after 15% cyclic stretch application. Furthermore, SRSF1-specific siRNA transfection reversed the VEGFA secretion induced by pathological high cyclic stretch. Our present results suggested that pathologically high cyclic stretch induces the shuttling of SRSF1 which results in the secretive pattern splicing of VEGFA and finally contributes to the proliferation of VSMCs.

Keywords

Hypertension Cyclic stretch Vascular endothelial growth factor A Vascular smooth muscle cells Serine/arginine-rich splicing factor 1.
Xie, Z.-W., Chen, Y.-X., Long, C.-F., Qi, Y.-X., & Yao, Q.-P. (2018). Cyclic stretch induces VEGFA alternative splicing via Serine/Arginine-Rich Splicing Factor 1. Cellular and Molecular Biology, 64(7), 43–50. https://doi.org/10.14715/cmb/2018.64.7.8
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX
References
  1. Lackland DT, Weber MA. Global Burden of Cardiovascular Disease and Stroke: Hypertension at the Core. Can J Cardiol 2015; 31: 569-71.
  2. Renna NF, Heras ND, Miatello R. Pathophysiology of vascular remodeling in hypertension. Int J Hypertens 2013; 2013 808353-59.
  3. Safar ME, Perronenu PA, Levenson JA, Toto-Moukouo JA, Simon AC. Pulsed Doppler: diameter, blood flow velocity, and volumic blood flow of the brachial artery in sustained essential hypertension. Circulation 1981; 63:393–400.
  4. Williams B. Mechanical influences on vascular smooth muscle cell function. J Hypertens 1998; 16:1921–29.
  5. Qi YX, Qu MJ, Yan ZQ, Zhao D, Jiang XH, Shen BR et al. Cyclic strain modulates migration and proliferation of vascular smooth muscle cells via Rho"GDIα, Rac1, and p38 pathway. J Cell Biochem 2010; 109: 906-14.
  6. Haga JH, Li YJ, Chien S. Molecular basis of the effects of mechanical stretch on vascular smooth muscle cells. J Biomech 2007; 40: 947-60.
  7. Schad JF, Meltzer KR, Hicks MR, Beutler DS, Cao TV, Standley PR. Cyclic strain upregulates VEGF and attenuates proliferation of vascular smooth muscle cells. Vasc Cell 2011; 3: 21-21.
  8. Yung YC, Chae J, Buehler MJ, Hunter CP, Mooney DJ. Cyclic tensile strain triggers a sequence of autocrine and paracrine signaling to regulate angiogenic sprouting in human vascular cells. Proc Natl Acad Sci U S A 2009; 106: 15279-84.
  9. Yao QP, Zhang P, Qi YX, Chen SG, Shen BR, Han Y et al. The role of SIRT6 in the differentiation of vascular smooth muscle cells in response to cyclic strain. Int J Biochem Cell Biol 2014; 98-104.
  10. Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov 2016; 15: 385-403.
  11. Ferrara N, Houck KA, Jakeman LB, Winer J, Leung DW. The vascular endothelial growth factor family of polypeptides. J Cell Biochem 1991; 47:211–18.
  12. Tober KL, Cannon RE, Spalding JW, Oberyszyn TM, Parrett ML, Rackoff AI et al. Comparative expression of novel vascular endothelial growth factor/vascular permeability factor transcripts in skin, papillomas, and carcinomas of v-Ha-ras Tg.AC transgenic mice and FVB/N mice. Biochem Biophys Res Commun 1998; 247: 644-53.
  13. Haigh JJ. Role of VEGF in organogenesis. Organogenesis, 2008, 4: 247-56.
  14. Ferrara N. Binding to the Extracellular Matrix and Proteolytic Processing: Two Key Mechanisms Regulating Vascular Endothelial Growth Factor Action. Mol Biol Cell 2010; 21: 687-90.
  15. Pan Q, Shai O, Lee LJ, Frey BJ, Blencowe BJ. Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat Genet 2008; 40: 1413-15.
  16. Kong SW, Hu YW, Ho JW, Ikeda S, Polster SP, John R, et al. Heart failure-associated changes in RNA splicing of sarcomere genes. Circ Cardiovasc Genet 2010; 3: 138-46.
  17. Cogan JD, Austin ED, Hedges L, Womack B, West J, Loyd JE, et al. Role of BMPR2 Alternative Splicing in Heritable Pulmonary Arterial Hypertension Penetrance. Circulation 2012; 126: 1907-16.
  18. Wan XJ, Zhao HC, Zhang P, Huo B, Shen BR, Yan ZQ, et al. Involvement of BK channel in differentiation of vascular smooth muscle cells induced by mechanical stretch. Int J Biochem Cell Biol 2015; 21-29.
  19. Jeong S. SR Proteins: Binders, Regulators, and Connectors of RNA. Mol Cells 2017; 40:1-9.
  20. Ning X, Min C, Dai R, Yan Z, Zhao H, Song Z, et al. SRSF1 promotes vascular smooth muscle cell proliferation through a Δ133p53/EGR1/KLF5 pathway. Nature Communications 2017; 8:16016.
  21. Barton CH, Ni Z, Vaziri ND. Enhanced nitric oxide inactivation in aortic coarctation-induced hypertension. Kidney Int 2001; 60: 1083-87.
  22. Mao X, Said R, Louis H, Max JP, Bourhim M, Challande P, et al. Cyclic stretch-induced thrombin generation by rat vascular smooth muscle cells is mediated by the integrin αvβ3 pathway. Cardiovasc Res 2012; 96: 513-23.
  23. Jayaraman S, Doucet M, Kominsky SL. Down-regulation of CITED2 attenuates breast tumor growth, vessel formation and TGF-β-induced expression of VEGFA. Oncotarget 2017; 8: 6169-78.
  24. Schlich R, Willems M, Greulich S, Ruppe F, Knoefel WT, Ouwens DM, et al. VEGF in the crosstalk between human adipocytes and smooth muscle cells: depot-specific release from visceral and perivascular adipose tissue. Mediators Inflamm 2013; 2013: 982458-982458.
  25. Fan J, Ponferrada VG, Sato T, Vemaraju S, Fruttiger M, Gerhardt H, et al. Crim1 maintains retinal vascular stability during development by regulating endothelial cell Vegfa autocrine signaling. Development 2014; 141:448-59.
  26. Stimpfl M, Tong D, Fasching B, Schuster E, Obermair A, Leodolter S, et al. Vascular Endothelial Growth Factor Splice Variants and Their Prognostic Value in Breast and Ovarian Cancer. Clin Cancer Res 2002; 8: 2253-59.
  27. Zhang H, Scott PA, Morbidelli L, Peak S, Moore J, Turley H, et al. The 121 amino acid isoform of vascular endothelial growth factor is more strongly tumorigenic than other splice variants in vivo. Br J Cancer 2000; 83: 63-68.
  28. Yuan A, Yu CJ, Kuo SH, Chen WJ, Lin FY, Luh KT, et al. Vascular endothelial growth factor 189 mRNA isoform expression specifically correlates with tumor angiogenesis, patient survival, and postoperative relapse in non-small-cell lung cancer. J Clin Oncol 2001; 19:432-41.
  29. Matlin AJ, Clark F, Smith CW. Understanding alternative splicing: towards a cellular code. Nat Rev Mol Cell Biol 2005; 6:386-98.
  30. Black DL. Mechanisms of Alternative Pre-Messenger RNA Splicing. Annu Rev Biochem 2003; 72: 291-336.
  31. Lopezmejia IC, Vautrot V, De TM, Behmansmant I, Bourgeois CF, Navarro CL, et al. A conserved splicing mechanism of the LMNA gene controls premature aging. Hum Mol Genet 2011; 20:4540-55.
  32. Sanford JR, Bruzik JP. Regulation of SR protein localization during development. Proc Natl Acad Sci U S A 2001; 98: 10184-89.
Read More

Author Biography

Qing-Ping Yao, Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University, Shanghai, China
Institute of Mechanobiology & Medical Engineering, School of Life Sciences & Biotechnology, Shanghai Jiao Tong University,Assistant Professor
Crossref
Scopus
Google Scholar
Europe PMC
Download this PDF file
PDF
Statistic
Read Counter : 715 Download : 379