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Endothelial nitric oxide synthase G894T gene polymorphism and response to skin reactive hyperemia

Rasool AH, Ghazali DM, Abdullah H, Halim AS, Wong AR

Microvasc Res, 2009 Sep;78(2):230-4.
PMID: 19481100 DOI: 10.1016/j.mvr.2009.05.005

Post occlusive skin reactive hyperemia (PORH) is a tool used to assess microcirculation. Endothelial nitric oxide synthase (eNOS) mediates nitric oxide (NO) production; polymorphism of the eNOS gene may affect response to the PORH process. This study aims to determine whether eNOS G894T gene polymorphism affects response to skin PORH. 230 normotensive male and females between 18 and 40 years participated in this cross-sectional study. 170 subjects were of the homozygous GG genotype, whereas 60 were of the GT genotype. Skin PORH was performed by occlusion of the upper arm at 200 mm Hg for 3 min. Skin perfusion and temperature were monitored before, during and after occlusion release using the laser Doppler fluximetry. There were no significant differences between genotypes in their baseline blood pressure, serum cholesterol, BMI and age. Maximum change in perfusion after occlusion release (PORHmax) for the GG and GT genotypes were not significantly different at 50.15+/-1.29 vs. 47.92+/-2.17 AU; ANCOVA, p=0.351. Peak perfusion (PORHpeak) were also not significantly different between the two genotypes (61.23+/-1.36 vs. 57.72+/-2.32 AU; p=0.169). Minimum baseline perfusion were however higher in the GG compared to the GT genotype (10.83+/-0.29 vs. 9.61+/-0.50, p=0.029). We conclude that microvascular reactivity, assessed by change in perfusion after temporary ischemia was not significantly different between the GG and GT genotypes of the eNOS G894T gene. eNOS 894T allele carriers however, have lower baseline perfusion compared to the homozygous G894 allele carrier.
Scopoletin, an active principle of tree tobacco (Nicotiana glauca) inhibits human tumor vascularization in xenograft models and modulates ERK1, VEGF-A, and FGF-2 in computer model

Tabana YM, Hassan LE, Ahamed MB, Dahham SS, Iqbal MA, Saeed MA, et al.

Microvasc Res, 2016 09;107:17-33.
PMID: 27133199 DOI: 10.1016/j.mvr.2016.04.009

We recently reported the antineovascularization effect of scopoletin on rat aorta and identified its potential anti-angiogenic activity. Scopoletin could be useful as a systemic chemotherapeutic agent against angiogenesis-dependent malignancies if its antitumorigenic activity is investigated and scientifically proven using a suitable human tumor xenograft model. In the present study, bioassay-guided (anti-angiogenesis) phytochemical investigation was conducted on Nicotiana glauca extract which led to the isolation of scopoletin. Further, anti-angiogenic activity of scopoletin was characterized using ex vivo, in vivo and in silico angiogenesis models. Finally, the antitumorigenic efficacy of scopoletin was studied in human colorectal tumor xenograft model using athymic nude mice. For the first time, an in vivo anticancer activity of scopoletin was reported and characterized using xenograft models. Scopoletin caused significant suppression of sprouting of microvessels in rat aortic explants with IC50 (median inhibitory concentration) 0.06μM. Scopoletin (100 and 200mg/kg) strongly inhibited (59.72 and 89.4%, respectively) vascularization in matrigel plugs implanted in nude mice. In the tumor xenograft model, scopoletin showed remarkable inhibition on tumor growth (34.2 and 94.7% at 100 and 200mg/kg, respectively). Tumor histology revealed drastic reduction of the extent of vascularization. Further, immunostaining of CD31 and NG2 receptors in the histological sections confirmed the antivascular effect of scopoletin in tumor vasculature. In computer modeling, scopoletin showed strong ligand affinity and binding energies toward the following angiogenic factors: protein kinase (ERK1), vascular endothelial growth factor A (VEGF-A), and fibroblast growth factor 2 (FGF-2). These results suggest that the antitumor activity of scopoletin may be due to its strong anti-angiogenic effect, which may be mediated by its effective inhibition of ERK1, VEGF-A, and FGF-2.
Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial cell function

Al-Salahi OS, Kit-Lam C, Majid AM, Al-Suede FS, Mohammed Saghir SA, Abdullah WZ, et al.

Microvasc Res, 2013 Nov;90:30-9.
PMID: 23899415 DOI: 10.1016/j.mvr.2013.07.007

Targeting angiogenesis could be an excellent strategy to combat angiogenesis-dependent pathophysiological conditions such as cancer, rheumatoid arthritis, obesity, systemic lupus erythematosus, psoriasis, proliferative retinopathy and atherosclerosis. Recently a number of clinical investigations are being undertaken to assess the potential therapeutic application of various anti-angiogenic agents. Many of these angiogenesis inhibitors are directed against the functions of endothelial cells, which are considered as the building blocks of blood vessels. Similarly, roots of a traditional medicinal plant, Eurycoma longifolia, can be used as an alternative treatment to prevent and treat the angiogenesis-related diseases. In the present study, antiangiogenic potential of partially purified quassinoid-rich fraction (TAF273) of E. longifolia root extract was evaluated using ex vivo and in vivo angiogenesis models and the anti-angiogenic efficacy of TAF273 was investigated in human umbilical vein endothelial cells (HUVEC). TAF273 caused significant suppression in sprouting of microvessels in rat aorta with IC50 11.5μg/ml. TAF273 (50μg/ml) showed remarkable inhibition (63.13%) of neovascularization in chorioallantoic membrane of chick embryo. Tumor histology also revealed marked reduction in extent of vascularization. In vitro, TAF273 significantly inhibited the major angiogenesis steps such as proliferation, migration and differentiation of HUVECs. Phytochemical analysis revealed high content of quassinoids in TAF273. Specially, HPLC characterization showed that TAF273 is enriched with eurycomanone, 13α(21)-epoxyeurycomanone and eurycomanol. These results demonstrated that the antiangiogenic activity of TAF273 may be due to its inhibitory effect on endothelial cell proliferation, differentiation and migration which could be attributed to the high content of quassinoids in E. longifolia.
Stemness and angiogenic gene expression changes of serial-passage human amnion mesenchymal cells

Fatimah SS, Tan GC, Chua K, Fariha MM, Tan AE, Hayati AR

Microvasc Res, 2013 Mar;86:21-9.
PMID: 23261754 DOI: 10.1016/j.mvr.2012.12.004

Particular attention has been directed towards human amnion mesenchymal stem cells (HAMCs) due to their accessibility, availability and immunomodulatory properties. Therefore, the aim of the present study was to determine the temporal changes of stemness and angiogenic gene expressions of serial-passage HAMCs.
Deregulation of hsa-miR-20b expression in TNF-α-induced premature senescence of human pulmonary microvascular endothelial cells

Wong PF, Jamal J, Tong KL, Khor ES, Yeap CE, Jong HL, et al.

Microvasc Res, 2017 11;114:26-33.
PMID: 28595801 DOI: 10.1016/j.mvr.2017.06.002

miRNAs are important regulators of cellular senescence yet the extent of their involvement remains to be investigated. We sought to identify miRNAs that are involved in cytokine-induced premature senescence (CIPS) in endothelial cells. CIPS was established in young human pulmonary microvascular endothelial cells (HMVEC-Ls) following treatment with a sublethal dose (20ng/ml) of tumor necrosis factor alpha (TNF-α) for 15days. In parallel, HMVEC-Ls were grown and routinely passaged until the onset of replicative senescence (RS). Differential expression analysis following miRNA microarray profiling revealed an overlapped of eight deregulated miRNAs in both the miRNA profiles of RS and TNF-α-induced premature senescence cells. Amongst the deregulated miRNAs were members of the miR 17-92 cluster which are known regulators of angiogenesis. The role of hsa-miR-20b in TNF-α-induced premature senescence, a paralog member of the miR 17-92 cluster, was further investigated. Biotin-labeled hsa-miR-20b captured the enriched transcripts of retinoblastoma-like 1 (RBL1), indicating that RBL1 is a target of hsa-miR-20b. Knockdown of hsa-miR-20b attenuated premature senescence in the TNF-α-treated HMVEC-Ls as evidenced by increased cell proliferation, increased RBL1 mRNA expression level but decreased protein expression of p16INK4a, a cellular senescence marker. These findings provide an early insight into the role of hsa-miR-20b in endothelial senescence.
Downregulation of Manic fringe impedes angiogenesis and cell migration of renal carcinoma

Chen WK, Oon CE, Kaur G, Sainson RCA, Li JL

Microvasc Res, 2022 Feb 11.
PMID: 35157839 DOI: 10.1016/j.mvr.2022.104341

Clear cell renal cell carcinoma (ccRCC) is a highly angiogenic cancer. Manic fringe (MFng) is elevated in ccRCC compared to the normal kidney. However, its role in ccRCC tumour angiogenesis remains elusive. This study seeks to determine the expression pattern of MFng in ccRCC blood vessels and its role in angiogenesis. The association between MFng and the blood vessels was established through online compendia, immunohistochemistry and qPCR analyses. The anti-angiogenic potential of lentiviral-mediated MFng knockdown in endothelial cells (EC shMFng) was assessed for viability, proliferation, apoptosis, migration, adhesion, cell cycle, vessel sprouting, and molecular expression of adhesion and apoptosis markers. Finally, EC shMFng were co-cultured with 786-0 renal cancer cells to determine their impact on cancer cell migration. The online dataset analyses and immunostaining on ccRCC tissues revealed high expression of MFng in ECs. MFng and CD31/PECAM-1 genes were up-regulated in ccRCC tissue samples compared to normal kidney tissues. EC shMFng demonstrated decreased cell viability due to G1 cell cycle arrest and reduced Ki-67 protein expression. In addition, shMFng down-regulated endothelial adhesion molecules and hindered EC migration, network formation and sprouting, compared to their respective empty vector (EV) controls. Co-culture assay of EC shMFng with 786-0 renal cancer cells inhibited cancer cell migration. These findings underscore the potential role of MFng in ECs in influencing renal cancer cell migration, thus opening an avenue for anti-angiogenic strategy targeting MFng to treat ccRCC.
Vitamin D deficiency enhances vascular oxidative stress, inflammation, and angiotensin II levels in the microcirculation of diabetic patients

Wee CL, Azemi AK, Mokhtar SS, Yahaya S, Yaacob NS, Rasool AHG

Microvasc Res, 2023 Nov;150:104574.
PMID: 37390963 DOI: 10.1016/j.mvr.2023.104574

Low vitamin D (vitD) levels have been reported to be a risk factor for diabetes-related cardiovascular complications. This study examined the effects of vitD deficiency on oxidative stress (OS), inflammation, and levels of the vasoconstrictor angiotensin II (Ang II) in the microvascular tissue of type 2 diabetic patients. Patients were categorized into (i) vitD non-deficient diabetics (DNP, n = 10) and (ii) vitD-deficient diabetics (DDP, n = 10), based on their serum 25(OH)D levels. Subcutaneous fat tissues with intact blood vessels were collected during lower limb surgical procedures. The blood vessel were isolated; measurements of the antioxidant enzyme superoxide dismutase (SOD) activity, OS marker malondialdehyde (MDA), Ang II, and the inflammatory marker, TNF-α of the microvascular tissues were determined. Elevated MDA levels and reduced SOD activity, with higher levels of TNF-α and Ang II were observed in the microvascular tissues of DDP compared to DNP. VitD deficiency did not associate with glycemic parameters (fasting blood glucose and glycated hemoglobin) levels. In conclusion, vitD deficiency was correlated with higher microvascular tissue OS, inflammation, and Ang II levels in type 2 diabetic patients. This may contribute to early vasculopathy that occurs in diabetic patients, thus, may contribute to the planning of therapeutic strategies to delay or prevent cardiovascular complications.
Vitamin D deficiency attenuates endothelial function by reducing antioxidant activity and vascular eNOS expression in the rat microcirculation

Wee CL, Mokhtar SS, Banga Singh KK, Rasool AHG

Microvasc Res, 2021 Nov;138:104227.
PMID: 34324883 DOI: 10.1016/j.mvr.2021.104227

This study examined the effects of vitamin D deficiency on vascular function and tissue oxidative status in the microcirculation; and whether or not these effects can be ameliorated with calcitriol, the active vitamin D metabolite. Three groups (n = 10 each) of male Sprague Dawley rats were fed for 10 weeks with control diet (CR), vitamin D-deficient diet without (DR), or with oral calcitriol supplementation (0.15 μg/kg) for the last four weeks (DSR). After 10 weeks, rats were sacrificed; mesenteric arterial rings were studied using wire myograph. Oxidative stress biomarkers malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured in the mesenteric arterial tissue. Vascular protein expression of endothelial nitric oxide synthase (eNOS) was determined by Western blotting. Acetylcholine-induced endothelium-dependent relaxation of DR was lower than CR. eNOS expression and SOD activity were lower in mesenteric arterial tissue of DR compared to CR. Calcitriol supplementation to DSR did not ameliorate the above parameters; in fact, augmented endothelium-dependent contraction was observed. Serum calcium was higher in DSR compared to CR and DR. In conclusion, vitamin D deficiency impaired microvascular vasodilation, associated with eNOS downregulation and reduced antioxidant activity. Calcitriol supplementation to vitamin D-deficient rats at the dosage used augmented endothelium-dependent contraction, possibly due to hypercalcaemia.
Pulse wave analysis as a tool to assess endothelial function following lipid lowering intervention in hypercholesterolemia

Ibrahim NNIN, Rasool AHG, Rahman RA, Azlan M, Aziz AA

Microvasc Res, 2024 Nov 23.
PMID: 39586372 DOI: 10.1016/j.mvr.2024.104772

BACKGROUND: Pulse wave analysis (PWA) assesses endothelial dependent vasodilation (EDV) via the change in augmentation index (AIx) and has been used as a tool to assess endothelial function. However, its effectiveness in assessing the response to lipid lowering treatment has not been evaluated. The study aimed to describe and correlate the change in EDV following lipid lowering intervention in patients with hypercholesterolemia.
METHODS: 48 newly diagnosed patients with hypercholesterolemia underwent 6 months intervention with statin and/or therapeutic lifestyle changes (TLC) in clinical setting. Lipid profile measurement and endothelial function assessment using PWA were performed pre- and post-intervention.
RESULTS: Significant reductions in low density lipoprotein cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C) and total cholesterol (TC) with corresponding significant improvement in EDV (2.94 ± 3.69 % to 7.50 ± 3.79 %, p