Intracranial aneurysm rupture causes severe disability and high mortality. Epidemiological studies show a strong association between decreased vitamin D levels and an increase in aneurysm rupture. However, the causality and mechanism remain largely unknown. In this study, we tested whether vitamin D deficiency promotes aneurysm rupture and examined the underlying mechanism for the protective role of vitamin D against the development of aneurysm rupture utilizing a mouse model of intracranial aneurysm. Mice consuming a vitamin D-deficient diet had a higher rupture rate than mice with a regular diet. Vitamin D deficiency increased proinflammatory cytokines in the cerebral arteries. Concurrently, vitamin D receptor knockout mice had a higher rupture rate than the corresponding wild-type littermates. The vitamin D receptors on endothelial and vascular smooth muscle cells, but not on hematopoietic cells, mediated the effect of aneurysm rupture. Our results establish that vitamin D protects against the development of aneurysmal rupture through the vitamin D receptors on vascular endothelial and smooth muscle cells. Vitamin D supplementation may be a viable pharmacologic therapy for preventing aneurysm rupture.
PakarinenS.Incidence, aetiology, and prognosis of primary subarachnoid haemorrhage. A study based on 589 cases diagnosed in a defined urban population during a defined period. Acta Neurol Scand1967;
43: 21–28.
2.
NieuwkampDJSetzLEAlgraA, et al.
Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol2009;
8: 635–642.
3.
ConnollyESJrRabinsteinAACarhuapomaJR, et al.
Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2012;
43: 1711–1737.
4.
FargenKMSoriano-BaronHERushingJT, et al.
A survey of intracranial aneurysm treatment practices among United States physicians. J Neurointerv Surg2018;
10: 44–49.
5.
WiebersDOWhisnantJPHustonJ, et al.
Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet2003;
362: 103–110.
6.
SuzukiTKamioYMakinoH, et al.
Prevention effect of antiplatelets on aneurysm rupture in a mouse intracranial aneurysm model. Cerebrovasc Dis2018;
45: 180–186.
7.
ThompsonBGBrownRDJrAmin-HanjaniS, et al.
Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke2015;
46: 2368–2400.
8.
MakinoHTadaYWadaK, et al.
Pharmacological stabilization of intracranial aneurysms in mice: a feasibility study. Stroke2012;
43: 2450–2456.
9.
HudsonJSMarincovichAJRoaJA, et al.
Aspirin and intracranial aneurysms. Stroke2019;
50: 2591–2596.
10.
CanARudyRFCastroVM, et al.
Association between aspirin dose and subarachnoid hemorrhage from saccular aneurysms: a case-control study. Neurology2018;
91: e1175–e1181.
11.
VinallPEMaislinGMicheleJJ, et al.
Seasonal and latitudinal occurrence of cerebral vasospasm and subarachnoid hemorrhage in the Northern hemisphere. Epidemiology1994;
5: 302–308.
12.
LaiPMDasenbrockHDuR.The association between meteorological parameters and aneurysmal subarachnoid hemorrhage: a nationwide analysis. PLoS One2014;
9: e112961.
13.
GuanJKarsyMEliI, et al.
Increased incidence of hypovitaminosis D among patients requiring treatment for cerebral aneurysms. World Neurosurg2016;
88: 15–20.
14.
MishraSMamourianA.Letter to the editor. Seasonal subarachnoid hemorrhage: temperature or daylight?J Neurosurg2017;
127: 231.
15.
BackesDRinkelGJAlgraA, et al.
Increased incidence of subarachnoid hemorrhage during cold temperatures and influenza epidemics. J Neurosurg2016;
125: 737–745.
16.
MacdonaldHMMavroeidiAFraserWD, et al.
Sunlight and dietary contributions to the seasonal vitamin D status of cohorts of healthy postmenopausal women living at northerly latitudes: a major cause for concern?Osteoporos Int2011;
22: 2461–2472.
17.
NanriAFooLHNakamuraK, et al.
Serum 25-hydroxyvitamin D concentrations and season-specific correlates in Japanese adults. J Epidemiol2011;
21: 346–353.
18.
WeiSYuanXLiD, et al.
Vitamin D level is associated with rupture of intracranial aneurysm in patients with subarachnoid hemorrhage. Front Neurol2022;
13: 890950.
19.
WeiSYuanXFanF, et al.
The relationship between the level of vitamin D and ruptured intracranial aneurysms. Sci Rep2021;
11: 11881.
20.
SharmaASharmaJK.Association of bone mineral density, vitamin D, and serum calcium in intracranial aneurysm. Asian J Neurosurg2020;
15: 521–526.
21.
KilkennyCBrowneWCuthillIC, et al.
Animal research: reporting in vivo experiments – the ARRIVE guidelines. J Cereb Blood Flow Metab2011;
31: 991–993.
22.
NukiYTsouTLKuriharaC, et al.
Elastase-induced intracranial aneurysms in hypertensive mice. Hypertension2009;
54: 1337–1344.
23.
KanematsuYKanematsuMKuriharaC, et al.
Critical roles of macrophages in the formation of intracranial aneurysm. Stroke2011;
42: 173–178.
24.
ShimadaKFurukawaHWadaK, et al.
Protective role of peroxisome proliferator-activated receptor-gamma in the development of intracranial aneurysm rupture. Stroke2015;
46: 1664–1672.
25.
TadaYWadaKShimadaK, et al.
Estrogen protects against intracranial aneurysm rupture in ovariectomized mice. Hypertension2014;
63: 1339–1344.
26.
ShimadaKFurukawaHWadaK, et al.
Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice. J Cereb Blood Flow Metab2015;
35: 1163–1168.
27.
YamamotoYYoshizawaTFukudaT, et al.
Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology2013;
154: 1008–1020.
28.
OhJRiekAEZhangRM, et al.
Deletion of JNK2 prevents vitamin-D-deficiency-induced hypertension and atherosclerosis in mice. J Steroid Biochem Mol Biol2018;
177: 179–186.
29.
BorgesCCSallesAFBringhentiI, et al.
Vitamin D deficiency increases lipogenesis and reduces beta-oxidation in the liver of diet-induced obese mice. J Nutr Sci Vitaminol (Tokyo)2018;
64: 106–115.
30.
WeishaarRESimpsonRU.Vitamin D3 and cardiovascular function in rats. J Clin Invest1987;
79: 1706–1712.
31.
TadaYMakinoHFurukawaH, et al.
Roles of estrogen in the formation of intracranial aneurysms in ovariectomized female mice. Neurosurgery2014;
75: 690–695; discussion 695.
32.
ShikataFShimadaKSatoH, et al.
Potential influences of gut microbiota on the formation of intracranial aneurysm. Hypertension2019;
73: 491–496.
33.
JiangHYangXWangY, et al.
Vitamin D protects against traumatic brain injury via modulating TLR4/MyD88/NF-kappaB pathway-mediated microglial polarization and neuroinflammation. Biomed Res Int2022;
2022: 3363036.
34.
GuoYXHeLYZhangM, et al.
1,25-Dihydroxyvitamin D3 regulates expression of LRP1 and RAGE in vitro and in vivo, enhancing Abeta1-40 brain-to-blood efflux and peripheral uptake transport. Neuroscience2016;
322: 28–38.
35.
AliAShahSAZamanN, et al.
Vitamin D exerts neuroprotection via SIRT1/nrf-2/NF-kB signaling pathways against D-galactose-induced memory impairment in adult mice. Neurochem Int2021;
142: 104893.
36.
NiWWattsSWNgM, et al.
Elimination of vitamin D receptor in vascular endothelial cells alters vascular function. Hypertension2014;
64: 1290–1298.
37.
RajasreeSUmashankarPRLalAV, et al.
1,25-dihydroxyvitamin D3 receptor is upregulated in aortic smooth muscle cells during hypervitaminosis D. Life Sci2002;
70: 1777–1788.
38.
KassiEAdamopoulosCBasdraEK, et al.
Role of vitamin D in atherosclerosis. Circulation2013;
128: 2517–2531.
39.
LaaksamoETulamoRLiimanA, et al.
Oxidative stress is associated with cell death, wall degradation, and increased risk of rupture of the intracranial aneurysm wall. Neurosurgery2013;
72: 109–117.
40.
SignorelliFSelaSGesualdoL, et al.
Hemodynamic stress, inflammation, and intracranial aneurysm development and rupture: a systematic review. World Neurosurg2018;
115: 234–244.
41.
StarkeRMChalouhiNDingD, et al.
Vascular smooth muscle cells in cerebral aneurysm pathogenesis. Transl Stroke Res2014;
5: 338–346.
42.
TukajSTrzonkowskiPTukajC.Regulatory effects of 1,25-dihydroxyvitamin D3 on vascular smooth muscle cells. Acta Biochim Pol2012;
59: 395–400.
43.
StarkeRMChalouhiNJabbourPM, et al.
Critical role of TNF-alpha in cerebral aneurysm formation and progression to rupture. J Neuroinflammation2014;
11: 77.
44.
AokiTKataokaHMoriwakiT, et al.
Role of TIMP-1 and TIMP-2 in the progression of cerebral aneurysms. Stroke2007;
38: 2337–2345.
45.
KrishnaSM.Vitamin D as a protector of arterial health: potential role in peripheral arterial disease formation. Int J Mol Sci2019;
20.
46.
TsuchihashiKTakizawaHToriiT, et al.
Hypoparathyroidism potentiates cardiovascular complications through disturbed calcium metabolism: possible risk of vitamin D(3) analog administration in dialysis patients with end-stage renal disease. Nephron2000;
84: 13–20.
47.
TadaYWadaKShimadaK, et al.
Roles of hypertension in the rupture of intracranial aneurysms. Stroke2014;
45: 579–586.
48.
DurhamALSpeerMYScatenaM, et al.
Role of smooth muscle cells in vascular calcification: implications in atherosclerosis and arterial stiffness. Cardiovasc Res2018;
114: 590–600.
49.
VoelklJLuongTTTuffahaR, et al.
SGK1 induces vascular smooth muscle cell calcification through NF-kappaB signaling. J Clin Invest2018;
128: 3024–3040.
50.
RahmaniRBaranoskiJFAlbuquerqueFC, et al.
Intracranial aneurysm calcification – a narrative review. Exp Neurol2022;
353: 114052.
51.
VoelklJLangFEckardtKU, et al.
Signaling pathways involved in vascular smooth muscle cell calcification during hyperphosphatemia. Cell Mol Life Sci2019;
76: 2077–2091.
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