Top

Published in:

01-06-2021 | Stroke | Original Article - Vascular Neurosurgery - Ischemia

Dilated microvessel with endothelial cell proliferation involves intraplaque hemorrhage in unstable carotid plaque

Authors: Daina Kashiwazaki, Shusuke Yamamoto, Naoki Akioka, Emiko Hori, Takashi Shibata, Naoya Kuwayama, Kyo Noguchi, Satoshi Kuroda

Published in: Acta Neurochirurgica | Issue 6/2021

Abstract

Background

The purpose of the present study was to clarify the characteristics of endothelial cell (EC) proliferation in intraplaque microvessels in vulnerable plaques and impact on clinical results.

Methods

The present study included 76 patients who underwent carotid endarterectomy. Patients were classified into three groups based on their symptoms: asymptomatic, symptomatic without recurrent ischemic event, and symptomatic with recurrent ischemic event. MR plaque imaging was performed and surgical specimens underwent immunohistochemical analysis. The number of CD31⁺ microvessels, and Ki67⁺ and CD105⁺ ECs in the carotid plaques was quantified, as measurements of maximum CD31⁺ microvessel diameter.

Results

MR plaque imaging yielded 41 subjects (54.0%) diagnosed with plaque with intraplaque hemorrhage (IPH), 14 subjects (18.4%) diagnosed with fibrous plaques, and 21 (27.6%) subjects diagnosed with lipid-rich plaques. The average largest diameter of microvessel in fibrous plaques, lipid-rich plaques, and plaque with IPH was 12.7 ± 4.1 μm, 31.3 ± 9.3 μm, and 56.4 ± 10.0 μm, respectively (p < 0.01). Dilated microvessels (>40 μm) were observed in 9.6% of plaques with IPH but only in 2.8% of lipid-rich plaques and 0% of fibrous plaques (p < 0.01). Ki67⁺/CD31⁺ ECs were identified in 2.8 ± 1.2% of fibrous plaques, 9.6 ± 6.9% of lipid-rich plaques, and in 19.5 ± 5.9% of plaques with IPH (p < 0.01). The average largest diameter of microvessels in the asymptomatic group was 17.1 ± 8.7 μm, 32.3 ± 10.8 μm in the symptomatic without recurrence group, and 55.2 ± 13.2 μm in the symptomatic with recurrence group (p < 0.01).

Conclusion

Dilated microvessels with proliferative ECs may play a key role in IPH pathogenesis. Furthermore, dilated microvessels are likely related to clinical onset and the recurrence of ischemic events. The purpose of the present study was to clarify the characteristics of EC proliferation in intraplaque microvessels in vulnerable plaques and their impact on clinical results, focusing on dilated intraplaque microvessels.

Altaf N, MacSweeney ST, Gladman J, Auer DP (2007) Carotid intraplaque hemorrhage predicts recurrent symptoms in patients with high-grade carotid stenosis. Stroke 38:1633–1635. https://doi.org/10.1161/STROKEAHA.106.473066CrossRefPubMed

Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, Charlton R, Parums DV, Jowett T, Marchuk DA, Burn J, Diamond AG (2000) Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 217:42–53. https://doi.org/10.1006/dbio.1999.9534CrossRefPubMed

Barbara NP, Wrana JL, Letarte M (1999) Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem 274:584–594. https://doi.org/10.1074/jbc.274.2.584CrossRefPubMed

Barnett JM, Suarez S, McCollum GW, Penn JS (2014) Endoglin promotes angiogenesis in cell- and animal-based models of retinal neovascularization. Invest Ophthalmol Vis Sci 55:6490–6498. https://doi.org/10.1167/iovs.14-14945CrossRefPubMedPubMedCentral

Cheifetz S, Bellon T, Cales C, Vera S, Bernabeu C, Massague J, Letarte M (1992) Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J Biol Chem 267:19027–19030CrossRef

de Vries MR, Quax PH (2016) Plaque angiogenesis and its relation to inflammation and atherosclerotic plaque destabilization. Curr Opin Lipidol 27:499–506. https://doi.org/10.1097/MOL.0000000000000339CrossRefPubMed

Guo M, Cai Y, Yao X, Li Z (2018) Mathematical modeling of atherosclerotic plaque destabilization: role of neovascularization and intraplaque hemorrhage. J Theor Biol 450:53–65. https://doi.org/10.1016/j.jtbi.2018.04.031CrossRefPubMed

Jaipersad AS, Lip GY, Silverman S, Shantsila E (2014) The role of monocytes in angiogenesis and atherosclerosis. J Am Coll Cardiol 63:1–11. https://doi.org/10.1016/j.jacc.2013.09.019CrossRefPubMed

Kashiwazaki D, Akioka N, Kuwayama N, Noguchi K, Tanaka K, Kuroda S (2015) Pathophysiology of acute cerebrovascular syndrome in patients with carotid artery stenosis: a magnetic resonance imaging/single-photon emission computed tomography study. Neurosurgery 76:427–433; discussion 433-424. https://doi.org/10.1227/NEU.0000000000000655CrossRefPubMed

10.

Kashiwazaki D, Akioka N, Kuwayama N, Hayashi T, Noguchi K, Tanaka K, Kuroda S (2016) Involvement of circulating endothelial progenitor cells in carotid plaque growth and vulnerability. J Neurosurg 125:1549–1556. https://doi.org/10.3171/2015.10.JNS151500CrossRefPubMed

11.

Kashiwazaki D, Koh M, Uchino H, Akioka N, Kuwayama N, Noguchi K, Kuroda S (2018) Hypoxia accelerates intraplaque neovascularization derived from endothelial progenitor cells in carotid stenosis. J Neurosurg:1–8. https://doi.org/10.3171/2018.4.JNS172876

12.

Kelly PJ, Camps-Renom P, Giannotti N, Marti-Fabregas J, Murphy S, McNulty J, Barry M, Barry P, Calvet D, Coutts SB, Cronin S, Delgado-Mederos R, Dolan E, Fernandez-Leon A, Foley S, Harbison J, Horgan G, Kavanagh E, Marnane M, McDonnell C, O'Donohoe M, Sharma V, Walsh C, Williams D, O'Connell M (2019) Carotid plaque inflammation imaged by (18)F-fluorodeoxyglucose positron emission tomography and risk of early recurrent stroke. Stroke 50:1766–1773. https://doi.org/10.1161/STROKEAHA.119.025422CrossRefPubMed

13.

Leroyer AS, Rautou PE, Silvestre JS, Castier Y, Leseche G, Devue C, Duriez M, Brandes RP, Lutgens E, Tedgui A, Boulanger CM (2008) CD40 ligand+ microparticles from human atherosclerotic plaques stimulate endothelial proliferation and angiogenesis a potential mechanism for intraplaque neovascularization. J Am Coll Cardiol 52:1302–1311. https://doi.org/10.1016/j.jacc.2008.07.032CrossRefPubMed

14.

Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (1999) Defective angiogenesis in mice lacking endoglin. Science 284:1534–1537. https://doi.org/10.1126/science.284.5419.1534CrossRefPubMed

15.

Li C, Issa R, Kumar P, Hampson IN, Lopez-Novoa JM, Bernabeu C, Kumar S (2003) CD105 prevents apoptosis in hypoxic endothelial cells. J Cell Sci 116:2677–2685. https://doi.org/10.1242/jcs.00470CrossRefPubMed

16.

Liu XS, Zhao HL, Cao Y, Lu Q, Xu JR (2012) Comparison of carotid atherosclerotic plaque characteristics by high-resolution black-blood MR imaging between patients with first-time and recurrent acute ischemic stroke. AJNR Am J Neuroradiol 33:1257–1261. https://doi.org/10.3174/ajnr.A2965CrossRefPubMedPubMedCentral

17.

Lu M, Peng P, Cui Y, Qiao H, Li D, Cai J, Zhao X (2018) Association of progression of carotid artery wall volume and recurrent transient ischemic attack or stroke: a magnetic resonance imaging study. Stroke 49:614–620. https://doi.org/10.1161/STROKEAHA.117.019422CrossRefPubMed

18.

Marioni G, Marino F, Giacomelli L, Staffieri C, Mariuzzi ML, Violino E, De Filippis C (2006) Endoglin expression is associated with poor oncologic outcome in oral and oropharyngeal carcinoma. Acta Otolaryngol 126:633–639. https://doi.org/10.1080/00016480500452558CrossRefPubMed

19.

Marioni G, D'Alessandro E, Giacomelli L, Staffieri A (2010) CD105 is a marker of tumour vasculature and a potential target for the treatment of head and neck squamous cell carcinoma. J Oral Pathol Med 39:361–367. https://doi.org/10.1111/j.1600-0714.2010.00888.xCrossRefPubMed

20.

Martin-Padura I, De Castellarnau C, Uccini S, Pilozzi E, Natali PG, Nicotra MR, Ughi F, Azzolini C, Dejana E, Ruco L (1995) Expression of VE (vascular endothelial)-cadherin and other endothelial-specific markers in haemangiomas. J Pathol 175:51–57. https://doi.org/10.1002/path.1711750109CrossRefPubMed

21.

Michel JB, Martin-Ventura JL, Nicoletti A, Ho-Tin-Noe B (2014) Pathology of human plaque vulnerability: mechanisms and consequences of intraplaque haemorrhages. Atherosclerosis 234:311–319. https://doi.org/10.1016/j.atherosclerosis.2014.03.020CrossRefPubMed

22.

Munoz-Chapuli R, Quesada AR, Angel Medina M (2004) Angiogenesis and signal transduction in endothelial cells. Cell Mol Life Sci 61:2224–2243. https://doi.org/10.1007/s00018-004-4070-7CrossRefPubMed

23.

Pages G, Pouyssegur J (2005) Transcriptional regulation of the vascular endothelial growth factor gene—a concert of activating factors. Cardiovasc Res 65:564–573. https://doi.org/10.1016/j.cardiores.2004.09.032CrossRefPubMed

24.

Parma L, Baganha F, Quax PHA, de Vries MR (2017) Plaque angiogenesis and intraplaque hemorrhage in atherosclerosis. Eur J Pharmacol 816:107–115. https://doi.org/10.1016/j.ejphar.2017.04.028CrossRefPubMed

25.

Saito A, Sasaki M, Ogasawara K, Kobayashi M, Hitomi J, Narumi S, Ohba H, Yamaguchi M, Kudo K, Terayama Y (2012) Carotid plaque signal differences among four kinds of T1-weighted magnetic resonance imaging techniques: a histopathological correlation study. Neuroradiology 54:1187–1194. https://doi.org/10.1007/s00234-012-1025-9CrossRefPubMed

26.

Schmidt D, von Hochstetter AR (1995) The use of CD31 and collagen IV as vascular markers. A study of 56 vascular lesions. Pathol Res Pract 191:410–414. https://doi.org/10.1016/S0344-0338(11)80727-2CrossRefPubMed

27.

Scholzen T, Gerdes J (2000) The Ki-67 protein: from the known and the unknown. J Cell Physiol 182:311–322. https://doi.org/10.1002/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9CrossRefPubMed

28.

Sedding DG, Boyle EC, Demandt JAF, Sluimer JC, Dutzmann J, Haverich A, Bauersachs J (2018) Vasa vasorum angiogenesis: key player in the initiation and progression of atherosclerosis and potential target for the treatment of cardiovascular disease. Front Immunol 9:706. https://doi.org/10.3389/fimmu.2018.00706CrossRefPubMedPubMedCentral

29.

Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, Rosenfeld ME, Schwartz CJ, Wagner WD, Wissler RW (1995) A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation 92:1355–1374. https://doi.org/10.1161/01.cir.92.5.1355CrossRefPubMed

30.

Takaya N, Yuan C, Chu B, Saam T, Polissar NL, Jarvik GP, Isaac C, McDonough J, Natiello C, Small R, Ferguson MS, Hatsukami TS (2005) Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. Circulation 111:2768–2775. https://doi.org/10.1161/CIRCULATIONAHA.104.504167CrossRefPubMed

31.

Wang C, Wang Q, Gao W, Zhang Z, Lou Y, Jin H, Chen X, Lei B, Xu H, Mao C (2018) Highly efficient local delivery of endothelial progenitor cells significantly potentiates angiogenesis and full-thickness wound healing. Acta Biomater 69:156–169. https://doi.org/10.1016/j.actbio.2018.01.019CrossRefPubMed

32.

Xu Y, Yuan C, Zhou Z, He L, Mi D, Li R, Cui Y, Wang Y, Wang Y, Liu G, Zheng Z, Zhao X (2016) Co-existing intracranial and extracranial carotid artery atherosclerotic plaques and recurrent stroke risk: a three-dimensional multicontrast cardiovascular magnetic resonance study. J Cardiovasc Magnetic Resonance 18:90. https://doi.org/10.1186/s12968-016-0309-3CrossRef

33.

Yoshida K, Narumi O, Chin M, Inoue K, Tabuchi T, Oda K, Nagayama M, Egawa N, Hojo M, Goto Y, Watanabe Y, Yamagata S (2008) Characterization of carotid atherosclerosis and detection of soft plaque with use of black-blood MR imaging. AJNR Am J Neuroradiol 29:868–874. https://doi.org/10.3174/ajnr.A1015CrossRefPubMed

Title: Dilated microvessel with endothelial cell proliferation involves intraplaque hemorrhage in unstable carotid plaque
Authors: Daina Kashiwazaki
Shusuke Yamamoto
Naoki Akioka
Emiko Hori
Takashi Shibata
Naoya Kuwayama
Kyo Noguchi
Satoshi Kuroda
Publication date: 01-06-2021
Publisher: Springer Vienna
Keywords: Stroke
Carotid Stenosis
Carotid Stenosis
Published in: Acta Neurochirurgica / Issue 6/2021
Print ISSN: 0001-6268
Electronic ISSN: 0942-0940
DOI: https://doi.org/10.1007/s00701-020-04595-0

At a glance: The STEP trials

Springer Medicine

Dilated microvessel with endothelial cell proliferation involves intraplaque hemorrhage in unstable carotid plaque

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2021

Arterial collateral anatomy predicts the risk for intra-operative changes in somatosensory evoked potentials in patients undergoing carotid endarterectomy: a prospective cohort study

Techniques and challenges of the expanded endoscopic endonasal sellar and parasellar approaches to invasive pituitary tumors

The annular closure device - panacea of lumbar disc herniation: how closed is closed enough for the intervertebral disc space?

Postural ergonomics and work-related musculoskeletal disorders in neurosurgery: lessons from an international survey

Differences in surgical outcome between petroclival meningioma and anterior petrous meningioma

Long-term outcome in meningiomas involving the major dural sinuses with combined therapy of subtotal resection and early postoperative gamma knife radiosurgery