Role of mechanosignaling on pathology of varicose vein

Saberianpour, Shirin; modaghegh, Mohamad Hadi Saeed; Rahimi, Hamidreza; Kamyar, Mohammad Mahdi

doi:10.1007/s12551-021-00783-z

Review
Published: 16 February 2021

Role of mechanosignaling on pathology of varicose vein

Shirin Saberianpour ORCID: orcid.org/0000-0002-6724-411X¹,
Mohamad Hadi Saeed modaghegh¹,
Hamidreza Rahimi^1,2 &
Mohammad Mahdi Kamyar¹

Biophysical Reviews volume 13, pages 139–145 (2021)Cite this article

491 Accesses
3 Citations
2 Altmetric
Metrics details

Abstract

Varicose veins are the most common vascular disease in humans. Veins have valves that help the blood return gradually to the heart without leaking blood. When these valves become weak, blood and fluid collect and pool by pressing against the walls of the veins, causing varicose veins. In the cardiovascular system, mechanical forces are important determinants of vascular homeostasis and pathological processes. Blood vessels are constantly exposed to a variety of hemodynamic forces, including shear stress and environmental strains caused by the blood flow. In varicose veins within the leg, venous blood pressure rises in the vein of the lower extremities due to prolonged standing, creating a peripheral tension in the vessel wall thereby causing mechanical stimulation of endothelial cells and vascular smooth muscle. Studies have shown that long-term increased exposure to vascular wall tension is associated with the overexpression of HIF-1α and HIF-2α and increased levels of MMP-2 and MMP-9, thereby reducing venous contraction and progressive venous dilatation, which is involved in the development of varicose veins. Following the expression of metalloproteinase, the expression of type 1 collagen increases, and the amount of type 3 collagen decreases. Therefore, collagen imbalance will cause the varicose veins to not stretch. Loss of structural proteins (type 3 collagen and elastin) in the vessel wall causes the loss of the biophysical properties of the varicose vein wall. This review article tries to elaborate on the effect of mechanical forces and sensors of these forces on the vascular wall in creating the mechanism of mechanosignaling, as well as the role of the onset of molecular signaling cascades in the pathology of varicose veins.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Abbreviations

MMP:: Matrix metallopeptidases
HIF:: Hypoxia-inducible factor-1alpha
FOXC2:: Forkhead box protein C2
MTHFR:: Methylene tetrahydrofolate reductase
CSK:: C-terminal Src kinase
ROS:: Reactive oxygen species
eNOS:: Endothelial NOS
ECM:: Extracellular matrix
RGD:: Arg-Gly-Asp
LOXL1:: Lysyl oxidase-like 1
VEGF:: Vascular endothelial growth factor

References

Asghar MY, Törnquist K (2020) Transient receptor potential canonical (TRPC) channels as modulators of migration and invasion. Int J Mol Sci 21:1739
CAS Article Google Scholar
Atta HM (2012, 2012) Varicose veins: role of mechanotransduction of venous hypertension. J Vasc Med. https://doi.org/10.1155/2012/538627
Behmoaras J, Slove S, Seve S, Vranckx R, Sommer P, Jacob M-P (2008) Differential expression of lysyl oxidases LOXL1 and LOX during growth and aging suggests specific roles in elastin and collagen fiber remodeling in rat aorta. Rejuvenation Res 11:883–889. https://doi.org/10.1089/rej.2008.0760
CAS Article PubMed Google Scholar
Birdina J, Pilmane M, Ligers A (2017) The morphofunctional changes in the wall of varicose veins. Ann Vasc Surg 42:274–284. https://doi.org/10.1016/j.avsg.2016.10.064
Article PubMed Google Scholar
Bradbury AW, Pappas PJ (2006) ‘Chronic venous insufficiency, varicose veins, lymphedema, and arteriovenous fistulas.’ In, Vascular Surgery (Springer). https://doi.org/10.1007/1-84628-008-7_10
Cario-Toumaniantz C, Boularan C, Schurgers LJ, Heymann M-F, Le Cunff M, Léger J, Loirand G, Pacaud P (2007) Identification of differentially expressed genes in human varicose veins: involvement of matrix gla protein in extracellular matrix remodeling. J Vasc Res 44:444–459. https://doi.org/10.1159/000106189
CAS Article PubMed Google Scholar
Cavallini, A (2019) Doctor, why do I have varicose veins?. Veins Lymph 8(1). https://doi.org/10.4081/vl.2019.7937
Cornu-Thenard A, Boivin P, Baud JM, de Vincenzi I, Carpentier PH (1994) Importance of the familial factor in varicose disease: clinical study of 134 families. J Dermatol Surg Oncol 20(5):318–326
Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ (1999) Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epidemiol Community Health 53:149–153. https://doi.org/10.1016/j.jvsv.2020.10.002
CAS Article PubMed PubMed Central Google Scholar
Fitts MK, Pike DB, Anderson K, Shiu Y-T (2014) Hemodynamic shear stress and endothelial dysfunction in hemodialysis access. Open Urol Nephrol J 7:33
Article Google Scholar
Fukaya E, Flores AM, Lindholm D, Gustafsson S, Zanetti D, Ingelsson E, Leeper NJ (2018) Clinical and genetic determinants of varicose veins: prospective, community-based study of ≈ 500 000 individuals. Circulation 138:2869–2880. https://doi.org/10.1161/CIRCULATIONAHA.118.035584
Article PubMed PubMed Central Google Scholar
Ghaderian SMH, Lindsey NJ, Graham AM, Homer-Vanniasinkam S, Najar RA (2010) Pathogenic mechanisms in varicose vein disease: the role of hypoxia and inflammation. Pathology 42:446–453. https://doi.org/10.3109/00313025.2010.493865
Article PubMed Google Scholar
Giancotti FG, Tarone G (2003) Positional control of cell fate through joint integrin/receptor protein kinase signaling. Annu Rev Cell Dev Biol 19:173–206. https://doi.org/10.1146/annurev.cellbio.19.031103.133334
CAS Article PubMed Google Scholar
Görmüs U, Timirci-Kahraman Ö, Arzu E, Kunt AT, Selim İ, Burak Dalan A, İsbir T (2014) Expression levels of elastin and related genes in human varicose veins. Folia Biol 60:68
Google Scholar
Goshchynsky VB, Migenko BO (2019) Pathophysiological and pathomorphological aspects of relapse of varicose veins after endovascular laser vein coagulation. Perspect Sci Educ 155
Hamann SAS, Mik L T-d, Fritschy WM, Kuiters GRR, Nijsten TEC, van den Bos RR (2019) Randomized clinical trial of endovenous laser ablation versus direct and indirect radiofrequency ablation for the treatment of great saphenous varicose veins. Br J Surg 106:998–1004. https://doi.org/10.1002/bjs.11187
CAS Article PubMed PubMed Central Google Scholar
Han B, Bai X-H, Lodyga M, Xu J, Yang BB, Keshavjee S, Post M, Liu M (2004) Conversion of mechanical force into biochemical signaling. J Biol Chem 279:54793–54801. https://doi.org/10.1074/jbc.M406880200
CAS Article PubMed Google Scholar
Hiraoka M, Kagawa Y (2017) Genetic polymorphisms and folate status. Congenital Anomal 57:142–149. https://doi.org/10.1111/cga.12232
CAS Article Google Scholar
Hu C, Lu K, Liu W (2020) Exendin-4 attenuates inflammation-mediated endothelial cell apoptosis in varicose veins through inhibiting the MAPK-JNK signaling pathway. J Recept Signal Transduct. https://doi.org/10.1080/10799893.2020.1756326
Ingber DE (2002) Mechanical signaling and the cellular response to extracellular matrix in angiogenesis and cardiovascular physiology. Circ Res 91:877–887. https://doi.org/10.1161/01.res.0000039537.73816.e5
CAS Article PubMed Google Scholar
Jacobs BN, Andraska EA, Obi AT, Wakefield TW (2017) Pathophysiology of varicose veins. J Vasc Surg: Venous Lymphatic Disord 5:460–467. https://doi.org/10.1016/j.jvsv.2016.12.014
Article Google Scholar
Karathanos C, Exarchou M, Tsezou A, Kyriakou D, Wittens C, Giannoukas A (2013) Factors associated with the development of superficial vein thrombosis in patients with varicose veins. Thromb Res 132:47–50. https://doi.org/10.1016/j.thromres.2013.05.017
CAS Article PubMed Google Scholar
Kim D-I, Eo H-S, Joh J-H (2005) Identification of differentially expressed genes in primary varicose veins. J Surg Res 123:222–226. https://doi.org/10.1016/j.jss.2004.08.003
CAS Article PubMed Google Scholar
Kockx MM, Knaapen MWM, Bortier HE, Cromheeke KM, Boutherin-Falson O, Finet M (1998) Vascular remodeling in varicose veins. Angiology 49:871–877. https://doi.org/10.1177/000331979804901101
CAS Article PubMed Google Scholar
Korkmaz Ö, Göksel S, Gül M, Başçil H, Yildir Y, Berkan Ö (2018) Does the use of N-butyl-2 cyanoacrylate in the treatment of lower extremity superficial varicose veins cause acute systemic inflammation and allergic reactions. Cardiovasc J Africa 29:213–217. https://doi.org/10.5830/CVJA-2018-012
Article Google Scholar
Kowalewski R, Malkowski A, Sobolewski K, Gacko M (2009) Evaluation of aFGF/bFGF and FGF signaling pathway in the wall of varicose veins. J Surg Res 155:165–172. https://doi.org/10.1016/j.jss.2008.07.032
CAS Article PubMed Google Scholar
Krysa J, Jones GT, Van Rij AM (2012) Evidence for a genetic role in varicose veins and chronic venous insufficiency. Phlebology 27:329–335. https://doi.org/10.1258/phleb.2011.011030
CAS Article PubMed Google Scholar
Kucukguven A, Khalil RA (2013) Matrix metalloproteinases as potential targets in the venous dilation associated with varicose veins. Curr Drug Targets 14:287–324
CAS PubMed PubMed Central Google Scholar
Laronha H, Caldeira J (2020) Structure and function of human matrix metalloproteinases. Cells 9:1076. https://doi.org/10.3390/cells9051076
CAS Article PubMed Central Google Scholar
Lee S, Lee W, Choe Y, Kim D, Na G, Kim J, Kim M, Kim J, Cho J (2005) Gene expression profiles in varicose veins using complementary DNA microarray. Dermatol Surg 31:391–395. https://doi.org/10.1111/j.1524-4725.2005.31103
CAS Article PubMed Google Scholar
Lim CS (2010) The hypoxia-inducible factor (HIF) pathway in varicose veins
Lim CS, Davies AH (2009) Pathogenesis of primary varicose veins. Br J Surg 96:1231–1242. https://doi.org/10.1002/bjs.6798
CAS Article PubMed Google Scholar
Liu X, Zhao Y, Gao J, Pawlyk B, Starcher B, Spencer JA, Yanagisawa H, Zuo J, Li T (2004) Elastic fiber homeostasis requires lysyl oxidase–like 1 protein. Nat Genet 36:178–182. https://doi.org/10.1038/ng1297
CAS Article PubMed Google Scholar
Ma Y, Choi J, Hourlier-Fargette A, Xue Y, Chung HU, Lee JY, Wang X, Xie Z, Kang D, Wang H (2018) Relation between blood pressure and pulse wave velocity for human arteries. Proc Natl Acad Sci 115:11144–11149. https://doi.org/10.1073/pnas.1814392115
CAS Article PubMed Google Scholar
MacColl E, Khalil RA et al Matrix metalloproteinases as regulators of vein structure and function: implications in chronic venous disease. J Pharmacol Exp Ther 355:410–428. https://doi.org/10.1124/jpet.115.227330
Martinac B (2014) The ion channels to cytoskeleton connection as potential mechanism of mechanosensitivity. Biochim Biophys Acta (BBA)-Biomembr 1838:682–691. https://doi.org/10.1016/j.bbamem.2013.07.015
CAS Article Google Scholar
Martinez-Lemus LA, Wu X, Wilson E, Hill MA, Davis GE, Davis MJ, Meininger GA (2003) Integrins as unique receptors for vascular control. J Vasc Res 40:211–233. https://doi.org/10.1159/000071886
CAS Article PubMed Google Scholar
McGhee BH, Bridges EJ (2002) Monitoring arterial blood pressure: what you may not know. Crit Care Nurse 22:60–79
Article Google Scholar
Metcalfe MJ, Baker DM, Turmaine M, Burnstock G (2007) Alterations in purinoceptor expression in human long saphenous vein during varicose disease. Eur J Vasc Endovasc Surg 33:239–250. https://doi.org/10.1016/j.ejvs.2006.09.007
CAS Article PubMed Google Scholar
Ng MYM, Andrew T, Spector TD, Jeffery S (2005) Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs. J Med Genet 42:235–239. https://doi.org/10.1136/jmg.2004.024075
CAS Article PubMed PubMed Central Google Scholar
Norouzpour A, Hooshyar Z, Mehdizadeh A (2013) Autoregulation of blood flow: vessel diameter changes in response to different temperatures. J Biomed Phys Eng 3:63
PubMed PubMed Central Google Scholar
Ortega MA, Romero B, Asúnsolo Á, Sainz F, Martinez-Vivero C, Álvarez-Mon M, Buján J, García-Honduvilla N (2018) 'Behavior of smooth muscle cells under hypoxic conditions: possible implications on the varicose vein endothelium. Biomed Res Int. https://doi.org/10.1155/2018/7156150
Pascual G, Mendieta C, García-Honduvilla N, Corrales C, Bellón JM, Buján J (2007) TGF-β1 upregulation in the aging varicose vein. J Vasc Res 44:192–201. https://doi.org/10.1159/000100375
CAS Article PubMed Google Scholar
Raffetto JD, Khalil RA (2008a) Mechanisms of varicose vein formation: valve dysfunction and wall dilation. Phlebology 23:85–98. https://doi.org/10.1258/phleb.2007.007027
CAS Article PubMed Google Scholar
Raffetto JD, Khalil RA (2008b) Matrix metalloproteinases in venous tissue remodeling and varicose vein formation. Curr Vasc Pharmacol 6:158–172. https://doi.org/10.2174/157016108784911957
CAS Article PubMed Google Scholar
Raffetto JD, Ross RL, Khalil RA (2007) Matrix metalloproteinase 2–induced venous dilation via hyperpolarization and activation of K+ channels: Relevance to varicose vein formation. J Vasc Surg 45:373–380. https://doi.org/10.1016/j.jvs.2006.10.041
Article PubMed PubMed Central Google Scholar
Raffetto JD, Qiao X, Koledova VV, Khalil RA (2008) Prolonged increases in vein wall tension increase matrix metalloproteinases and decrease constriction in rat vena cava: potential implications in varicose veins. J Vasc Surg 48:447–456. https://doi.org/10.1016/j.jvs.2008.03.004
Article PubMed PubMed Central Google Scholar
Sadick NS (1992) Predisposing factors of varicose and telangiectatic leg veins. J Dermatol Surg Oncol 18:883–886. https://doi.org/10.1111/j.1524-4725.1992.tb02921.x
CAS Article PubMed Google Scholar
Sansilvestri-Morel P, Rupin A, Jullien ND, Lembrez N, Mestries-Dubois P, Fabiani JN, Verbeuren TJ (2005) Decreased production of collagen Type III in cultured smooth muscle cells from varicose vein patients is due to a degradation by MMPs: possible implication of MMP-3. J Vasc Res 42:388–398. https://doi.org/10.1159/000087314
CAS Article PubMed Google Scholar
Sayer GL, Smith PDC (2004) 'Immunocytochemical characterisation of the inflammatory cell infiltrate of varicose veins. Eur J Vasc Endovasc Surg 28:479–483. https://doi.org/10.1016/j.ejvs.2004.07.023
CAS Article PubMed Google Scholar
Schlaepfer DD, Jones KC, Hunter T (1998) Multiple Grb2-mediated integrin-stimulated signaling pathways to ERK2/mitogen-activated protein kinase: summation of both c-Src-and focal adhesion kinase-initiated tyrosine phosphorylation events. Mol Cell Biol 18:2571–2585
CAS Article Google Scholar
Segiet OA, Brzozowa-Zasada M, Piecuch A, Dudek D, Reichman-Warmusz E, Wojnicz R (2015) Biomolecular mechanisms in varicose veins development. Ann Vasc Surg 29:377–384. https://doi.org/10.1016/j.avsg.2014.10.009
Article PubMed Google Scholar
Shadrina AS, Sharapov SZ, Shashkova TI, Tsepilov YA (2019) Varicose veins of lower extremities: Insights from the first large-scale genetic study. PLoS Genet 15:e1008110. https://doi.org/10.1371/journal.pgen.1008110
CAS Article PubMed PubMed Central Google Scholar
Sharif-Naeini R, Dedman A, Folgering JHA, Duprat F, Patel A, Nilius B, Honoré E (2008) TRP channels and mechanosensory transduction: insights into the arterial myogenic response. Pflügers Archiv-Eur J Physiol 456:529–540. https://doi.org/10.1007/s00424-007-0432-y
CAS Article Google Scholar
Shyu K-G (2009) Cellular and molecular effects of mechanical stretch on vascular cells and cardiac myocytes. Clin Sci 116:377–389. https://doi.org/10.1042/CS20080163
CAS Article Google Scholar
Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78:539–552. https://doi.org/10.1016/j.bcp.2009.04.029
CAS Article PubMed PubMed Central Google Scholar
Stennett AK, Qiao X, Falone AE, Koledova VV, Khalil RA (2009) Increased vascular angiotensin type 2 receptor expression and NOS-mediated mechanisms of vascular relaxation in pregnant rats. Am J Phys Heart Circ Phys 296:H745–HH55. https://doi.org/10.1152/ajpheart.00861.2008
CAS Article Google Scholar
Travers JP, Brookes CE, Evans J, Baker DM, Kent C, Makin GS, Mayhew TM (1996) Assessment of wall structure and composition of varicose veins with reference to collagen, elastin and smooth muscle content. Eur J Vasc Endovasc Surg 11:230–237. https://doi.org/10.1016/s1078-5884(96)80058-x
CAS Article PubMed Google Scholar
Wali MA, Eid RA (2001) Smooth muscle changes in varicose veins: an ultrastructural study. J Smooth Muscle Res 37:123–135. https://doi.org/10.1540/jsmr.37.123
CAS Article PubMed Google Scholar
Wang N, Butler JP, Ingber DE (1993) Mechanotransduction across the cell surface and through the cytoskeleton. Science 260:1124–1127. https://doi.org/10.1126/science.7684161
CAS Article PubMed Google Scholar
Wang Y-H, Yan Z-Q, Qi Y-X, Cheng B-B, Wang X-D, Zhao D, Shen B-R, Jiang Z-L (2010) Normal shear stress and vascular smooth muscle cells modulate migration of endothelial cells through histone deacetylase 6 activation and tubulin acetylation. Ann Biomed Eng 38:729–737. https://doi.org/10.1007/s10439-009-9896-6
Article PubMed Google Scholar
Ward JPT, Knock GA, Snetkov VA, Aaronson PI (2004) Protein kinases in vascular smooth muscle tone—role in the pulmonary vasculature and hypoxic pulmonary vasoconstriction. Pharmacol Ther 104:207–231. https://doi.org/10.1016/j.pharmthera.2004.08.009
CAS Article PubMed Google Scholar
Williams SA, Wasserman S, Rawlinson DW, Kitney RI, Smaje LH, Tooke JE (1988) Dynamic measurement of human capillary blood pressure. Clin Sci 74:507–512. https://doi.org/10.1042/cs0740507
CAS Article Google Scholar
Wilmanns C, Cooper A, Wockner L, Katsandris S, Glaser N, Meyer A, Bartsch O, Binder H, Walter PK, Zechner U (2015) Morphology and progression in primary varicose vein disorder due to 677C > T and 1298A > C variants of MTHFR. EBioMedicine 2:158–164. https://doi.org/10.1016/j.ebiom.2015.01.006
Article PubMed PubMed Central Google Scholar
Xu J, Shi G-P (2014) Vascular wall extracellular matrix proteins and vascular diseases. Biochim Biophys Acta (BBA)-Molec Basis Dis:1842, 2106–1819. https://doi.org/10.1016/j.bbadis.2014.07.008
Yokota A, Gamoh S, Tanaka-Totoribe N, Shiba T, Kuwabara M, Nakamura E, Hayase T, Hisa H, Nakamura K, Yamamoto R (2016) Angiotensin II, as well as 5-hydroxytriptamine, is a potent vasospasm inducer of saphenous vein graft for coronary artery bypass grafting in patients with diabetes mellitus. Biochem Biophys Rep 6:82–87. https://doi.org/10.1016/j.bbrep.2016.03.008
CAS Article PubMed PubMed Central Google Scholar
Zhu R, Niu H, Yin N, Wu T, Zhao Y (2019) Analysis of varicose veins of lower extremities based on vascular endothelial cell inflammation images and multi-scale deep learning. IEEE Access 7:174345–174358. https://doi.org/10.1109/ACCESS.2019.2954708
Article Google Scholar

Download references

Author information

Authors and Affiliations

Vascular and Endovascular Surgery Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
Shirin Saberianpour, Mohamad Hadi Saeed modaghegh, Hamidreza Rahimi & Mohammad Mahdi Kamyar
Department of Medical Genetics and Molecular Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Hamidreza Rahimi

Authors

Shirin Saberianpour
View author publications
You can also search for this author in PubMed Google Scholar
Mohamad Hadi Saeed modaghegh
View author publications
You can also search for this author in PubMed Google Scholar
Hamidreza Rahimi
View author publications
You can also search for this author in PubMed Google Scholar
Mohammad Mahdi Kamyar
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shirin Saberianpour.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Saberianpour, S., modaghegh, M.H.S., Rahimi, H. et al. Role of mechanosignaling on pathology of varicose vein. Biophys Rev 13, 139–145 (2021). https://doi.org/10.1007/s12551-021-00783-z

Download citation

Received: 13 November 2020
Accepted: 05 January 2021
Published: 16 February 2021
Issue Date: February 2021
DOI: https://doi.org/10.1007/s12551-021-00783-z

Keywords

Varicose
Veins
Mechanosignaling