Open Access

Astaxanthin inhibits homocysteine‑induced endothelial cell dysfunction via the regulation of the reactive oxygen species‑dependent VEGF‑VEGFR2‑FAK signaling pathway

  • Authors:
    • Xian‑Jun Wang
    • Da‑Chen Tian
    • Feng‑Wen Wang
    • Meng‑Hao Zhang
    • Cun‑Dong Fan
    • Wang Chen
    • Mei‑Hong Wang
    • Xiao‑Yan Fu
    • Jin‑Kui Ma
  • View Affiliations

  • Published online on: April 12, 2019     https://doi.org/10.3892/mmr.2019.10162
  • Pages: 4753-4760
  • Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Increased plasma levels of homocysteine (Hcy) can cause severe damage to vascular endothelial cells. Hcy‑induced endothelial cell dysfunction contributes to the occurrence and development of human cerebrovascular diseases (CVDs). Our previous studies have revealed that astaxanthin (ATX) exhibits novel cardioprotective activity against Hcy‑induced cardiotoxicity in vitro and in vivo. However, the protective effect and mechanism of ATX against Hcy‑induced endothelial cell dysfunction requires further investigation. In the present study, treatment of human umbilical vascular endothelial cells (HUVECs) with Hcy inhibited the migration, invasive and tube formation potentials of these cells in a dose‑dependent manner. Hcy treatment further induced a time‑dependent increase in the production of reactive oxygen species (ROS), and downregulated the expression of vascular endothelial growth factor (VEGF), phosphorylated (p)‑Tyr‑VEGF receptor 2 (VEGFR2) and p‑Tyr397‑focal adhesion kinase (FAK). On the contrary, ATX pre‑treatment significantly inhibited Hcy‑induced cytotoxicity and increased HUVEC migration, invasion and tube formation following Hcy treatment. The mechanism of action may involve the effective inhibition of Hcy‑induced ROS generation and the recovery of FAK phosphorylation. Collectively, our findings suggested that ATX could inhibit Hcy‑induced endothelial dysfunction by suppressing Hcy‑induced activation of the VEGF‑VEGFR2‑FAK signaling axis, which indicates the novel therapeutic potential of ATX in treating Hcy‑mediated CVD.

References

1 

Fateeva VV and Vorobyova OV: Nitric oxide: From the mechanism of action to pharmacological effects in cerebrovascular diseases. Zh Nevrol Psikhiatr Im S S Korsakova. 117:131–135. 2017.(In Russian). View Article : Google Scholar : PubMed/NCBI

2 

Poggesi A, Pasi M, Pescini F, Pantoni L and Inzitari D: Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. J Cereb Blood Flow Metab. 36:72–94. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Holm H, Nägga K, Nilsson ED, Ricci F, Melander O, Hansson O, Bachus E, Magnusson M and Fedorowski A: Biomarkers of microvascular endothelial dysfunction predict incident dementia: A population-based prospective study. J Intern Med. 282:94–101. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Michinaga S and Koyama Y: Protection of the Blood-Brain barrier as a therapeutic strategy for brain damage. Biol Pharm Bull. 40:569–575. 2017. View Article : Google Scholar : PubMed/NCBI

5 

Spencer JI, Bell JS and DeLuca GC: Vascular pathology in multiple sclerosis: Reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry. 89:42–52. 2018. View Article : Google Scholar : PubMed/NCBI

6 

Nezu T, Hosomi N, Aoki S, Kubo S, Araki M, Mukai T, Takahashi T, Maruyama H, Higashi Y and Matsumoto M: Endothelial dysfunction is associated with the severity of cerebral small vessel disease. Hypertens Res. 38:291–297. 2015. View Article : Google Scholar : PubMed/NCBI

7 

Dayal S, Baumbach GL, Arning E, Bottiglieri T, Faraci FM and Lentz SR: Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia. PLoS One. 12:e01757322017. View Article : Google Scholar : PubMed/NCBI

8 

Hatefi M, Behzadi S, Dastjerdi MM, Ghahnavieh AA, Rahmani A, Mahdizadeh F, Hafezi Ahmadi MR and Asadollahi K: Correlation of homocysteine with cerebral hemodynamic abnormality, endothelial dysfunction markers, and cognition impairment in patients with traumatic brain injury. World Neurosurg. 97:70–79. 2017. View Article : Google Scholar : PubMed/NCBI

9 

Škovierová H, Vidomanová E, Mahmood S, Sopková J, Drgová A, Červeňová T, Halašová E and Lehotský J: The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci. 17(pii): E17332016. View Article : Google Scholar : PubMed/NCBI

10 

Catena C, Colussi G, Url-Michitsch M, Nait F and Sechi LA: Subclinical carotid artery disease and plasma homocysteine levels in patients with hypertension. J Am Soc Hypertens. 9:167–175. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Wang BR, Ou Z, Jiang T, Zhang YD, Zhao HD, Tian YY, Shi JQ and Zhou JS: Independent correlation of serum homocysteine with cerebral microbleeds in patients with acute ischemic stroke due to large-artery atherosclerosis. J Stroke Cerebrovasc Dis. 25:2746–2751. 2016. View Article : Google Scholar : PubMed/NCBI

12 

Wu GH, Kong FZ, Dong XF, Wu DF, Guo QZ, Shen AR, Cheng QZ and Luo WF: Association between hyperhomocysteinemia and stroke with atherosclerosis and small artery occlusion depends on homocysteine metabolism-related vitamin levels in Chinese patients with normal renal function. Metab Brain Dis. 32:859–865. 2017. View Article : Google Scholar : PubMed/NCBI

13 

Zhang Z, Wei C, Zhou Y, Yan T, Wang Z, Li W and Zhao L: Homocysteine induces apoptosis of human umbilical vein endothelial cells via mitochondrial dysfunction and endoplasmic reticulum stress. Oxid Med Cell Longev. 2017:57365062017. View Article : Google Scholar : PubMed/NCBI

14 

Yan TT, Li Q, Zhang XH, Wu WK, Sun J, Li L, Zhang Q and Tan HM: Homocysteine impaired endothelial function through compromised vascular endothelial growth factor/Akt/endothelial nitric oxide synthase signalling. Clin Exp Pharmacol Physiol. 37:1071–1077. 2010. View Article : Google Scholar : PubMed/NCBI

15 

Pan L, Yu G, Huang J, Zheng X and Xu Y: Homocysteine inhibits angiogenesis through cytoskeleton remodeling. Biosci Rep. 37(pii): BSR201708602017. View Article : Google Scholar : PubMed/NCBI

16 

Oosterbaan AM, Steegers EA and Ursem NT: The effects of homocysteine and folic acid on angiogenesis and VEGF expression during chicken vascular development. Microvasc Res. 83:98–104. 2012. View Article : Google Scholar : PubMed/NCBI

17 

Zhang Q, Li Q, Chen Y, Huang X, Yang IH, Cao L, Wu WK and Tan HM: Homocysteine-impaired angiogenesis is associated with VEGF/VEGFR inhibition. Front Biosci (Elite Ed). 4:2525–2535. 2012.PubMed/NCBI

18 

Chen CH, Beard RS and Bearden SE: Homocysteine impairs endothelial wound healing by activating metabotropic glutamate receptor 5. Microcirculation. 19:285–295. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Rodrıguez-Nieto S, Chavarrıa T, Martınez-Poveda B, Sánchez-Jiménez F, Rodríguez Quesada A and Medina MA: Anti-angiogenic effects of homocysteine on cultured endothelial cells. Biochem Biophys Res Commun. 293:497–500. 2002. View Article : Google Scholar : PubMed/NCBI

20 

Fan CD, Sun JY, Fu XT, Hou YJ, Li Y, Yang MF, Fu XY and Sun BL: Astaxanthin attenuates homocysteine-induced cardiotoxicity in vitro and in vivo by inhibiting mitochondrial dysfunction and oxidative damage. Front Physiol. 8:10412017. View Article : Google Scholar : PubMed/NCBI

21 

Pang X, Si J, Xu S, Li Y and Liu J: Simvastatin inhibits homocysteine-induced CRP generation via interfering with the ROS-p38/ERK1/2 signal pathway in rat vascular smooth muscle cells. Vascul Pharmacol. 88:42–47. 2017. View Article : Google Scholar : PubMed/NCBI

22 

Tian X, Zhao L, Song X, Yan Y, Liu N, Li T, Yan B and Liu B: HSP27 inhibits homocysteine-induced endothelial apoptosis by modulation of ROS production and mitochondrial Caspase-dependent apoptotic pathway. Biomed Res Int. 2016:48478742016. View Article : Google Scholar : PubMed/NCBI

23 

Zhang M, Cui Z, Cui H, Wang Y and Zhong C: Astaxanthin protects astrocytes against trauma-induced apoptosis through inhibition of NKCC1 expression via the NF-κB signaling pathway. BMC Neurosci. 18:422017. View Article : Google Scholar : PubMed/NCBI

24 

Nai Y, Liu H, Bi X, Gao H and Ren C: Protective effect of astaxanthin on acute cerebral infarction in rats. Hum Exp Toxicol. 37:929–936. 2018. View Article : Google Scholar : PubMed/NCBI

25 

Zhang M, Cui Z, Cui H, Cao Y, Zhong C and Wang Y: Astaxanthin alleviates cerebral edema by modulating NKCC1 and AQP4 expression after traumatic brain injury in mice. BMC Neurosci. 17:602016. View Article : Google Scholar : PubMed/NCBI

26 

Lee DH, Lee YJ and Kwon KH: Neuroprotective effects of astaxanthin in oxygen-glucose deprivation in SH-SY5Y cells and global cerebral ischemia in rat. J Clin Biochem Nutr. 47:121–129. 2010. View Article : Google Scholar : PubMed/NCBI

27 

Liu X and Osawa T: Astaxanthin protects neuronal cells against oxidative damage and is a potent candidate for brain food. Forum Nutr. 61:129–135. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Lu YP, Liu SY, Sun H, Wu XM, Li JJ and Zhu L: Neuroprotective effect of astaxanthin on H(2)O(2)-induced neurotoxicity in vitro and on focal cerebral ischemia in vivo. Brain Res. 1360:40–48. 2010. View Article : Google Scholar : PubMed/NCBI

29 

Shen H, Kuo CC, Chou J, Delvolve A, Jackson SN, Post J, Woods AS, Hoffer BJ, Wang Y and Harvey BK: Astaxanthin reduces ischemic brain injury in adult rats. FASEB J. 23:1958–1968. 2009. View Article : Google Scholar : PubMed/NCBI

30 

Wen X, Huang A, Hu J, Zhong Z, Liu Y, Li Z, Pan X and Liu Z: Neuroprotective effect of astaxanthin against glutamate-induced cytotoxicity in HT22 cells: Involvement of the Akt/GSK-3β pathway. Neuroscience. 303:558–568. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Wu Q, Zhang XS, Wang HD, Zhang X, Yu Q, Li W, Zhou ML and Wang XL: Astaxanthin activates nuclear factor erythroid-related factor 2 and the antioxidant responsive element (Nrf2-ARE) pathway in the brain after subarachnoid hemorrhage in rats and attenuates early brain injury. Mar Drugs. 12:6125–6141. 2014. View Article : Google Scholar : PubMed/NCBI

32 

Zhang XS, Zhang X, Wu Q, Li W, Wang CX, Xie GB, Zhou XM, Shi JX and Zhou ML: Astaxanthin offers neuroprotection and reduces neuroinflammation in experimental subarachnoid hemorrhage. J Surg Res. 192:206–213. 2014. View Article : Google Scholar : PubMed/NCBI

33 

Zhang XS, Zhang X, Wu Q, Li W, Zhang QR, Wang CX, Zhou XM, Li H, Shi JX and Zhou ML: Astaxanthin alleviates early brain injury following subarachnoid hemorrhage in rats: Possible involvement of Akt/bad signaling. Mar Drugs. 12:4291–4310. 2014. View Article : Google Scholar : PubMed/NCBI

34 

Zhang XS, Zhang X, Zhou ML, Zhou XM, Li N, Li W, Cong ZX, Sun Q, Zhuang Z, Wang CX and Shi JX: Amelioration of oxidative stress and protection against early brain injury by astaxanthin after experimental subarachnoid hemorrhage. J Neurosurg. 121:42–54. 2014. View Article : Google Scholar : PubMed/NCBI

35 

Bi YL, Mi PY, Zhao SJ, Pan HM, Li HJ, Liu F, Shao LR, Zhang HF, Zhang P and Jiang SL: Salinomycin exhibits anti-angiogenic activity against human glioma in vitro and in vivo by suppressing the VEGF-VEGFR2-AKT/FAK signaling axis. Int J Mol Med. 39:1255–1261. 2017. View Article : Google Scholar : PubMed/NCBI

36 

Lai WK and Kan MY: Homocysteine-induced endothelial dysfunction. Ann Nutr Metab. 67:1–12. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Tiwari A, Pattanaik N, Mohanty Jaiswal A and Dixit M: Increased FRG1 expression reduces in vitro cell migration, invasion and angiogenesis, ex vivo supported by reduced expression in tumors. Biosci Rep. 37(pii): BSR201710622017. View Article : Google Scholar : PubMed/NCBI

38 

Bai Y, Bai L, Zhou J, Chen H and Zhang L: Sequential delivery of VEGF, FGF-2 and PDGF from the polymeric system enhance HUVECs angiogenesis in vitro and CAM angiogenesis. Cell Immunol. 323:19–32. 2018. View Article : Google Scholar : PubMed/NCBI

39 

Heldin J, O'Callaghan P, Hernández Vera R, Fuchs PF, Gerwins P and Kreuger J: FGD5 sustains vascular endothelial growth factor A (VEGFA) signaling through inhibition of proteasome-mediated VEGF receptor 2 degradation. Cell Signal. 40:125–132. 2017. View Article : Google Scholar : PubMed/NCBI

40 

Lv J, Sun B, Mai Z, Jiang M and Du J: STAT3 potentiates the ability of airway smooth muscle cells to promote angiogenesis by regulating VEGF signalling. Exp Physiol. 102:598–606. 2017. View Article : Google Scholar : PubMed/NCBI

41 

Mahecha AM and Wang H: The influence of vascular endothelial growth factor-A and matrix metalloproteinase-2 and-9 in angiogenesis, metastasis, and prognosis of endometrial cancer. Onco Targets Ther. 10:4617–4624. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Tang F, Pacheco MTF, Chen P, Liang D and Li W: Secretogranin III promotes angiogenesis through MEK/ERK signaling pathway. Biochem Biophys Res Commun. 495:781–786. 2018. View Article : Google Scholar : PubMed/NCBI

43 

Abdelzaher LA, Imaizumi T, Suzuki T, Tomita K, Takashina M and Hattori Y: Astaxanthin alleviates oxidative stress insults-related derangements in human vascular endothelial cells exposed to glucose fluctuations. Life Sci. 150:24–31. 2016. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

June 2019
Volume 19 Issue 6

Print ISSN: 1791-2997
Online ISSN:1791-3004

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, X., Tian, D., Wang, F., Zhang, M., Fan, C., Chen, W. ... Ma, J. (2019). Astaxanthin inhibits homocysteine‑induced endothelial cell dysfunction via the regulation of the reactive oxygen species‑dependent VEGF‑VEGFR2‑FAK signaling pathway. Molecular Medicine Reports, 19, 4753-4760. https://doi.org/10.3892/mmr.2019.10162
MLA
Wang, X., Tian, D., Wang, F., Zhang, M., Fan, C., Chen, W., Wang, M., Fu, X., Ma, J."Astaxanthin inhibits homocysteine‑induced endothelial cell dysfunction via the regulation of the reactive oxygen species‑dependent VEGF‑VEGFR2‑FAK signaling pathway". Molecular Medicine Reports 19.6 (2019): 4753-4760.
Chicago
Wang, X., Tian, D., Wang, F., Zhang, M., Fan, C., Chen, W., Wang, M., Fu, X., Ma, J."Astaxanthin inhibits homocysteine‑induced endothelial cell dysfunction via the regulation of the reactive oxygen species‑dependent VEGF‑VEGFR2‑FAK signaling pathway". Molecular Medicine Reports 19, no. 6 (2019): 4753-4760. https://doi.org/10.3892/mmr.2019.10162