Transforming growth factor beta in patients with cervical artery dissection

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OBJECTIVE

To evaluate transforming growth factor beta (TGF-β) in patients with cervical artery dissection (CeAD).

MATERIAL AND METHODS

TGF-β was studied by enzyme immunoassay in 74 of 336 patients with CeAD observed at the Research Center of Neurology (Moscow) from 2000 to 2021. The average patient’s age at the time of TGF-β study was 41.6±9.8 years; the proportion of women was 51%. TGF-β was studied in the first month of the disease (n=9), for 2—3 months (n=12) and at a later period (mean — 4.3±5.03 years) (n=53). The control group consisted of 20 healthy volunteers, matched for age and sex. Dissection occurred in internal carotid artery (ICA) (n=42), vertebral artery (VA) (n=29), ICA+VA (n=3) and involved 1 artery (n=58) or 2—3 arteries (n=16). Clinical manifestations included ischemic stroke (IS) (n=49), isolated cervical-cephalic headache (n=23), lower cranial nerve palsy (n=2). Pathological CeAD tortuosity was detected by angiography in 13 patients, and a dissecting aneurysm in 15 patients.

RESULTS

TGF-β1 and TGF-β2 were elevated in patients with CeAD patients compared with the control: TGF-β1 — 4990 [3950; 7900] pg/ml vs. 3645 [3230; 4250] pg/ml, p=0.001; TGF-β2 — 6120 [4680; 7900] pg/ml vs. 3155 [2605; 4605] pg/ml, p=0.001. The highest TGF-β1 and TGF-β2 levels were noted at 2—3 months of the disease. There was no correlation between the TGF-β level and various clinical and angiographic parameters.

CONCLUSION

Increased TGF-β level confirms that CeAD patients have connective tissue disorder that underlies the arterial wall weakness. A higher TGF-β level at 2—3 months of CeAD seems to be connected with an active reparative process in arterial wall after dissection. TGF-β can be used as a biomarker of connective tissue dysplasia in patients with CeAD.

Keywords:

TGF-β

connective tissue dysplasia

dissection

ischemic stroke

young age

Authors:

Kalashnikova L.A.

Research Center of Neurology

ORCID: 0000-0003-1142-0548

Danilova M.S.

Research Center of Neurology

Shabalina A.A.

Research Center of Neurology

SPIN RSCI: 9414-9068
Scopus AuthorID: 59097027100
ResearcherID: B-2504-2018
ORCID: 0000-0001-9604-7775

Gubanova M.V.

Research Center of Neurology

Shamtieva K.V.

Research Center of Neurology

Dreval M.V.

Research Center of Neurology

Dobrynina L.A.

Research Center of Neurology

ORCID: 0000-0001-9929-2725

Received:

20.04.2022

Accepted:

08.07.2022

List of references:

Kalashnikova LA, Dobrynina LA. Dissection of brain arteries: ischemic stroke and other clinical manifestations. M.: Izd-vo «Vako»; 2013:208. (In Russ.).
Dobrynina LA, Kalashnikova LA, Pavlova LN. Causes of ischemic stroke in young adults. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2011;111(3):4-8. (In Russ.).
Kalashnikova LA, Dobrynina LA. Ischemic stroke in young adults. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2017;117(8):3-12. (In Russ.). https://doi.org/10.17116/jnevro2017117823-12
Lee VH, Brown RD Jr, Mandrekar JN, et al. Incidence and outcome of cervical artery dissection: a population-based study. Neurology. 2006 Nov 28;67(10):1809-1812. https://doi.org/10.1212/01.wnl.0000244486.30455.71
Putaala J, Metso AJ, Metso TM, et al. Analysis of 1008 consecutive patients aged 15 to 49 with first-ever ischemic stroke: the Helsinki young stroke registry. Stroke. 2009;40(4):1195-1203. https://doi.org/10.1161/STROKEAHA.108.529883
Debette S, Leys D. Cervical-artery dissections: predisposing factors, diagnosis, and outcome. Lancet Neurol. 2009;8(7):668-678. https://doi.org/10.1016/S1474-4422(09)70084-5
Debette S. Pathophysiology and risk factors of cervical artery dissection: what have we learnt from large hospital-based cohorts? Curr Opin Neurol. 2014;27(1):20-28. https://doi.org/10.1097/WCO.0000000000000056
de Bray JM, Marc G, Pautot V, et al. Fibromuscular dysplasia may herald symptomatic recurrence of cervical artery dissection. Cerebrovasc Dis. 2007;23(5-6):448-452. https://doi.org/10.1159/000101470
Arnold M, Camus-Jacqmin M, Stapf C, et al. Postpartum cervicocephalic artery dissection. Stroke. 2008;39(8):2377-9237. https://doi.org/10.1161/STROKEAHA.107.510107
Kalashnikova LA, Gulevskaya TS, Konovalov RN, et al. Lower cranial nerve palsias in the internal carotid artery dissection. Annals of Clinical and Experimental Neurology. 2008;1:22-27. (In Russ.).
Kalashnikova LA, Gulevskaya TS, Anufriev PL, et al. Ischemic stroke in young age due to dissection of intracranial carotid artery and its branches (clinical and morphological study). Annals of Clinical and Experimental Neurology. 2009;3(1):18-24. (In Russ.).
Kalashnikova LA, Chajkovskaya RP, Dobrynina LA, et al. Dissection of the internal carotid artery as a cause of severe ischemic stroke with a fatal outcome (clinical and pathomorphological study). Zhurnal nevrologii i psihiatrii im. S.S. Korsakova. 2015;115:12:34-38. (In Russ.). https://doi.org/10.17116/jnevro201511512219-25
Kalashnikova LA, Chaĭkovskaia RP, Gulevskaia TS, et al. Intimal rupture of the displastic middle cerebral artery wall complicated by thrombosis and fatal ischemic stroke. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2018;118(3-2):9-14. (In Russ.). https://doi.org/10.17116/jnevro2018118329-14
Brandt T, Orberk E, Weber R, et al. Pathogenesis of cervical artery dissections: Association with connective tissue abnormalities. Neurology. 2001;57:24-30. https://doi.org/10.1212/WNL.57.1.24
Giossi A, Ritelli M, Costa P, et al. Connective tissue anomalies in patients with spontaneous cervical artery dissection. Neurology. 2014;83(22):2032-2037. https://doi.org/10.1212/WNL.0000000000001030
Gubanova MV, Kalashnikova LA, Dobrynina LA, et al. Markers of connective tissue dysplasia in dissection of the main arteries of the head and provoking factors of dissection. Annaly klinicheskoj i jeksperimental’noj nevrologii. 2017;11(4):19-28. (In Russ.). https://doi.org/10.18454/ACEN.2017.4.2.
Debette S, Goeggel Simonetti B, Schilling S, et al. CADISP-plus consortium. Familial occurrence and heritable connective tissue disorders in cervical artery dissection. Neurology. 2014 Nov 25;83(22):2023-2031. https://doi.org/10.1212/WNL.0000000000001027
Kalashnikova LA, Sakharova AV, Dobrynina LA, et al. Mitochondrial arteriopathy as a cause of spontaneous dissection of cerebral arteries. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2010;110(4 Suppl 2):3-11. (In Russ.).
Kalashnikova LA, Sakharova AV, Dobrynina LA, et al. Ultrastructural changes of skin arteries in patients with spontaneous cerebral artery dissection. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2011;111(7):54-60. (In Russ.).
Sakharova AV, Kalashnikova LA, Chaykovskaya RP, et al. Morphological signs of mitochondrial cytopathy in skeletal muscles and micro-vessels in a patient with cerebral artery dissection associated with MELAS syndrome. Arkhiv patologii. 2010;74(2):51-56. (In Russ.).
Tay SH, Nordli DR Jr, Bonilla E, et al. Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Arch Neurol. 2006;63(2):281-283. https://doi.org/10.1001/archneur.63.2.281
Gubanova MV, Kalashnikova LA, Dobrynina LA, et al. Biomarkers of connective tissue dysplasia in patients with the dissection of carotid and vertebral arteries. In: Materials of the XI All-Russian Congress of Neurologists and IV Congress of the National Associations Against Stroke. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2019;119:395. (In Russ.).
McEntee CP, Gunaltay S, Travis MA. Regulation of barrier immunity and homeostasis by integrin-mediated transforming growth factor β activation. Immunology. 2020;160(2):139-148. https://doi.org/10.1111/imm.13162
Tzavlaki K, Moustakas A. TGF-β Signaling. Biomolecules. 2020;10(3):487. https://doi.org/10.3390/biom10030487
Nabel EG, Shum L, Pompili VJ, et al. Direct transfer of transforming growth factor beta 1 gene into arteries stimulates fibrocellular hyperplasia. Proc Natl Acad Sci USA. 1993;90(22):10759-10763. https://doi.org/10.1073/pnas.90.22.10759
Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology. Cold Spring Harb Perspect Biol. 2016;8(5):a021873. https://doi.org/10.1101/cshperspect.a021873
Lichtman MK, Otero-Vinas M, Falanga V. Transforming growth factor beta (TGF-β) isoforms in wound healing and fibrosis. Wound Repair Regen. 2016;24(2):215-222. https://doi.org/10.1111/wrr.12398
Benke K, Ágg B, Szilveszter B, et al. Loeys-Dietz syndrome. Adv Exp Med Biol. 2014;802:95-105. https://doi.org/10.1007/978-94-007-7893-1_7
Wagner AH, Zaradzki M, Arif R, et al. Marfan syndrome: A therapeutic challenge for long-term care. Biochem Pharmacol. 2019 Jun;164:53-63. https://doi.org/10.1016/j.bcp.2019.03.034
Mallat Z, Ait-Oufella H, Tedgui A. The Pathogenic Transforming Growth Factor-β Overdrive Hypothesis in Aortic Aneurysms and Dissections: A Mirage? Circ Res. 2017;120(11):1718-1720. https://doi.org/10.1161/CIRCRESAHA.116.310371
Zeigler SM, Sloan B, Jones JA. Pathophysiology and Pathogenesis of Marfan Syndrome. Adv Exp Med Biol. 2021;1348:185-206. https://doi.org/10.1007/978-3-030-80614-9_8
Ganesh SK, Morissette R, Xu Z, et al. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features. FASEB J. 2014;28(8):3313-3324. https://doi.org/10.1096/fj.14-251207
Pezzini A, Drera B, Del Zotto E, et al. Mutations in TGFBR2 gene cause spontaneous cervical artery dissection. J Neurol Neurosurg Psychiatry. 2011;82(12):1372-1374. https://doi.org/10.1136/jnnp.2010.231902
Robertson JJ, Koyfman A. Cervical Artery Dissections: A Review. J Emerg Med. 2016;51(5):508-518. https://doi.org/10.1016/j.jemermed.2015.10.044
Kalashnikova LA, Gulevskaya TS, Sakharova AV, et al. Internal carotid and vertebral artery dissection: morphology, pathophysiology and provoking factors. Bulletin of RSMU. 2019;(5):78-85. (In Russ.). https://doi.org/10.24075/brsmu.2019.064
Kloss M, Grond-Ginsbach C, Ringleb P, et al. Recurrence of cervical artery dissection: An underestimated risk. Neurology. 2018;90(16):e1372-e1378. https://doi.org/10.1212/WNL.0000000000005324
Kalashnikova LA, Dobrynina LA, Maksimova MYu, et al. Internal carotid and vertebral artery dissection: an approach to patient management. Annals of clinical and experimental neurology. 2021;15(1):5-12. (In Russ.). https://doi.org/10.25692/ACEN.2021.1.1
Pakyari M, Farrokhi A, Maharlooei MK, Ghahary A. Critical Role of Transforming Growth Factor Beta in Different Phases of Wound Healing. Adv Wound Care (New Rochelle). 2013;2(5):215-224. https://doi.org/10.1089/wound.2012.0406
Gubanova MV, Kalashnikova LA, Dobrynina LA. Fibromuscular dysplasia and its neurological manifestations. Zhurnal Nevrologii i Psikhiatrii imeni S.S. Korsakova. 2020;120(11):116-123. (In Russ.). https://doi.org/10.17116/jnevro2020120111116
Bonacina S, Locatelli M, Mazzoleni V, et al. Spontaneous cervical artery dissection and fibromuscular dysplasia: Epidemiologic and biologic evidence of a mutual relationship. Trends Cardiovasc Med. 2022;32(2):103-109. https://doi.org/10.1016/j.tcm.2021.01.006

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