Is the Adventitial Vasa Vasorum in Vulnerable Carotid Plaques Increased or Decreased?

doi:10.37015/AUDT.2025.240043

Abstract

Abstract:

Background Intraplaque neovascularization is a biomarker of vulnerable plaque. However, no data are available whether the increase in neovascularization within carotid plaques is a result of ischemia or an increase in adventitial vasa vasorum (VV).

Objective To evaluate the VV signal in carotid vulnerable plaques.

Methods Contrast-enhanced ultrasound (CEUS) examination was performed to examine changes in VV density in 47 patients with carotid plaque, and 21 patients received CT angiography (CTA) examination to assess the VV signal. In addition, a single-channel flow tissue model was fabricated for use in vitro studies to exclude pseudo-enhancement interferences in the distal wall of arteries by CEUS.

Results The intensities of adventitial VV behind carotid plaque were lower than that of adventitial VV at the same level adjacent to the plaque in both CEUS and CTA examinations (P < 0.05). In vitro study, the intensities of far wall increased as the microbubble concentration increased (P < 0.05). However, no significant differences of intensities of far wall were found between different thicknesses tubes at the concentration of microbubble concentrations of 0.3% and 0.5% (P ≥ 0.05).

Conclusion The formation of intraplaque neovascularization in carotid arteries is associated with the adventitial VV, and ischemia of VV may be a potential mechanism for intraplaque neovascularization.

Key words: Carotid vulnerable plaque; Contrast-enhanced ultrasound; Vasa vasorum; Neovascularization

Wang Yixuan, Jin Lin, Chen Jianxiong, Yang Huixian, Shen Cuiqin, Xu Wenzhe, Shen Yuzhou, Huang Jun, Sun Liwan, Du Lianfang, Wang Bei, Li Fan, Li Zhaojun. Is the Adventitial Vasa Vasorum in Vulnerable Carotid Plaques Increased or Decreased?. Advanced Ultrasound in Diagnosis and Therapy, 2025, 9(1): 56-64.

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References 23

[1]	Campbell BCV, Khatri P. Stroke. Lancet (London, England) 2020;396:129-142.
[2]	Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2019;394:1145-1158.
[3]	Heistad DD, Marcus ML, Larsen GE, Armstrong ML. Role of vasa vasorum in nourishment of the aortic wall. Am J Physiol 1981;240:H781-787.
[4]	Subbotin VM. Excessive intimal hyperplasia in human coronary arteries before intimal lipid depositions is the initiation of coronary atherosclerosis and constitutes a therapeutic target. Drug Discov Today 2016;21:1578-1595.
[5]	Li Z, Bai Y, Li W, Gao F, Kuang Y, Du L, et al. Carotid vulnerable plaques are associated with circulating leukocytes in acute ischemic stroke patients: an clinical study based on contrast-enhanced ultrasound. Sci Rep 2018;8:8849.
[6]	Staub D, Partovi S, Schinkel AF, Coll B, Uthoff H, Aschwanden M, et al. Correlation of carotid artery atherosclerotic lesion echogenicity and severity at standard US with intraplaque neovascularization detected at contrast-enhanced US. Radiology 2011;258:618-626.
[7]	Sluimer JC, Gasc JM, van Wanroij JL, Kisters N, Groeneweg M, Sollewijn Gelpke MD, et al. Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis. J Am Coll Cardiol 2008;51:1258-1265.
[8]	Wu X, Reboll MR, Korf-Klingebiel M, Wollert KC. Angiogenesis after acute myocardial infarction. Cardiovasc Res 2021;117:1257-1273.
[9]	Thapar A, Shalhoub J, Averkiou M, Mannaris C, Davies AH, Leen EL. Dose-dependent artifact in the far wall of the carotid artery at dynamic contrast-enhanced US. Radiology 2012;262:672-679.
[10]	Saba L, Cau R, Murgia A, Nicolaides AN, Wintermark M, Castillo M, et al. Carotid plaque-RADS: A novel stroke risk classification system. JACC Cardiovasc Imaging 2024;17:62-75.
[11]	Boyle EC, Sedding DG, Haverich A. Targeting vasa vasorum dysfunction to prevent atherosclerosis. Vascular pharmacology 2017;96-98:5-10.
[12]	Sedding DG, Boyle EC, Demandt JAF, Sluimer JC, Dutzmann J, Haverich A, et al. Vasa vasorum angiogenesis: Key player in the initiation and progression of atherosclerosis and potential target for the treatment of cardiovascular disease. Front Immunol 2018;9:706.
[13]	Jorgensen SM, Korinek MJ, Vercnocke AJ, Anderson JL, Halaweish A, Leng S, et al. Arterial wall perfusion measured with photon counting spectral X-ray CT. Proc SPIE Int Soc Opt Eng 2016;9967.
[14]	Zheng L, Yang WJ, Niu CB, Zhao HL, Wong KS, Leung TWH, et al. Correlation of adventitial vasa vasorum with intracranial atherosclerosis: A postmortem study. Journal of stroke 2018;20:342-349.
[15]	Ito H, Wakatsuki T, Yamaguchi K, Fukuda D, Kawabata Y, Matsuura T, et al. Atherosclerotic coronary plaque is associated with adventitial vasa vasorum and local inflammation in adjacent epicardial adipose tissue in fresh cadavers. Circ J 2020;84:769-775.
[16]	Sano M, Sasaki T, Baba S, Inuzuka K, Katahashi K, Kayama T, et al. Differences in vasa vasorum distribution in human aortic aneurysms and atheromas. Angiology 2022;73:546-556.
[17]	Chistiakov DA, Melnichenko AA, Myasoedova VA, Grechko AV, Orekhov AN. Role of lipids and intraplaque hypoxia in the formation of neovascularization in atherosclerosis. Ann Med 2017;49:661-677.
[18]	Ritman EL, Lerman A. The dynamic vasa vasorum. Cardiovasc Res 2007;75:649-658.
[19]	Tesfamariam B. Periadventitial local drug delivery to target restenosis. Vascul Pharmacol 2017:S1537- 1891(17)30235-5.
[20]	Schinkel AFL, Bosch JG, Staub D, Adam D, Feinstein SB. Contrast-enhanced ultrasound to assess carotid intraplaque neovascularization. Ultrasound Med Biol 2020;46:466-478.
[21]	Magnoni M, Coli S, Marrocco-Trischitta MM, Melisurgo G, De Dominicis D, Cianflone D, et al. Contrast-enhanced ultrasound imaging of periadventitial vasa vasorum in human carotid arteries. Eur J Echocardiogr 2009;10:260-264.
[22]	Staub D, Patel MB, Tibrewala A, Ludden D, Johnson M, Espinosa P, et al. Vasa vasorum and plaque neovascularization on contrast-enhanced carotid ultrasound imaging correlates with cardiovascular disease and past cardiovascular events. Stroke 2010;41:41-47.
[23]	ten Kate GL, Renaud GG, Akkus Z, van den Oord SC, ten Cate FJ, Shamdasani V, et al. Far-wall pseudoenhancement during contrast-enhanced ultrasound of the carotid arteries: clinical description and in vitro reproduction. Ultrasound Med Biol 2012;38:593-600.

Item	Without cerebral infarction (n = 19)	With cerebral infarction (n = 28)	t/ꭓ²	P value
Gender(F/M)	7/12	5/23	1.263	0.261
Age, y	64.37 ± 6.66	67.43 ± 7.90	-1.385	0.173
Height, cm	166.66 ± 8.12	170.30 ± 6.85	-1.660	0.104
Weight, kg	62.90 ± 9.11	67.13 ± 9.64	-1.511	0.138
BMI	22.63 ± 2.80	23.04 ± 2.31	-5.45	0.588
SBP, mm Hg	144.05 ± 14.52	143.25 ± 19.72	0.152	0.880
DBP, mm Hg	90.11 ± 8.82	89.54 ± 11.81	0.179	0.859
PP, mm Hg	53.95 ± 6.61	53.71 ± 9.38	0.094	0.926
Hypertension(with/without)^*	6/11	11/13	0.455	0.500
Diabetes(with/without)^※	5/12	8/16	0.071	0.790
US characteristics
Plaque thickness, mm	3.07 ± 1.03	3.28 ± 1.15	-0.645	0.522
Plaque length, mm	11.39 ± 5.72	11.17 ± 5.01	0.141	0.889
Plaque echogenicity			1.070	1.000
Hypoechoic	7	11
Isoechoic	0	1
Hyperechoic	1	1
Mixed echogenicity	11	15
CEUS characteristics
ROI_plaque	-41.75 ± 6.11	-43.09 ± 10.35	0.556	0.581
ROI	-39.00 ± 6.50	-38.83 ± 8.76	-0.075	0.940

Number	Gender(F/M)	Age (y)	The length of plaque (mm)	The width of plaque (mm)	The location of plaque	Cerebral infarction (Yes/No)
1	M	72	27.40	5.8	RICA	Yes
2	M	83	20.30	5.2	LICA	Yes
3	M	80	27.80	5.7	RICA	Yes
4	M	71	19.70	5.4	LICA	Yes
5	M	69	14.30	5.6	LICA	NO
6	M	60	23.90	6.1	RICA	Yes
7	M	64	26.30	4.6	RICA	Yes
8	M	63	6.79	4.07	LICA	Yes
9	F	72	23.20	5.1	LICA	Yes
10	M	65	14.50	4.1	LICA	Yes
11	M	55	28.30	4.9	LICA	NO
12	M	74	14.60	5.3	LECA	Yes
13	F	89	18.70	5.5	RICA	Yes
14	M	86	12.40	3.6	RICA	Yes
15	M	64	26.30	5.1	LICA	Yes
16	M	66	22.70	5.7	RICA	Yes
17	M	59	20.90	5.6	RICA	Yes
18	M	70	33.50	4.6	LICA	NO
19	M	82	8.20	4.3	RICA	Yes
20	M	78	19.30	4.8	LICA	Yes
21	M	62	17.10	5.4	RICA	Yes

Imaging modality	CT value of vascular wall behind the dominant plaque	CT value of ipsilateral wall of dominant plaque	CT value of contralateral wall of dominant plaque	CT value of adjacent wall of dominant plaque	CT value of shoulder of plaque	CT value of bottom of plaque	CT value of center of plaque
CT plain scan	44.68 ± 8.02	50.42 ± 7.63	51.71 ± 7.93	50.42 ± 7.63	38.78 ± 7.43	38.08 ± 6.33	26.30 ± 8.43
Enhanced CT scan	43.48 ± 10.15^*	71 ± 17.65	82.31 ± 21.34	71.00 ± 17.65	64.33 ± 12.33	46.75 ± 10.86	32.40 ± 9.71
T value	0.425	-4.905	-6.186	-4.905	-8.138	-3.161	-2.173
P value	0.673	<0.001	<0.001	<0.001	<0.001	0.003	0.036

ROI	Wall thickness	Concentration			Z value	P value
ROI	Wall thickness	0.05%	0.30%	0.5%	Z value	P value
ROInear-wall	2 mm	0.77 (-1.10,1.28)	-0.73 (0.94,0.38)	0.01 (-0.32,0.47)	3.796	0.15
	3 mm	0.28 (0.05,0.98)	0.17 (-0.06,0.31)	0.04 (-0.05,0.19)	2.023	0.364
ROIlumen	2 mm	6.51 (6.35,7.50)	14.05 (13.69,14.29)^*	16.92 (16.44,17.29)^*※	25.806	< 0.001
	3 mm	6.07 (5.84,6.37)^ф	12.70 (12.51,13.14)^*ф	14.82 (14.43,15.05)^*ф	23.484	< 0.001
ROIfar-wall	2 mm	0.44 (-0.12,0.60)	3.42 (1.84,8.97)^*	9.02 (6.35,12.78)^*	20.999	< 0.001
	3 mm	0.90 (0.34,2.14)^ф	2.68 (2.19,3.49)	11.02 (9.51,12.72)^*※	21.835	< 0.001

Item	ROInear-wall	ROIlumen	ROIfar-wall
ROInear-wall	r =1.000	r = -0.231	r = 0.221
	-	P = 0.075	P = 0.090
ROIlumen	r = -0.231	r =1.000	r = 0.775
	P = 0.075	-	P < 0.001
ROIfar-wall	r = 0.221	r = 0.775	r = 1.000
	P = 0.090	P < 0.001	-