Matthias Frick

Statins differentially regulate vascular endothelial growth factor synthesis in endothelial and vascular smooth muscle cells

OBJECTIVESnHMG-CoA reductase inhibitors (statins) can modulate the formation of new blood vessels, but the reports on their contribution to angiogenesis are contradictory. Therefore, we investigated whether the effect of statins is dependent either on the concentration of the drug or on the cell type.nnnMETHODS AND RESULTSnUnder basal conditions human vascular smooth muscle cells (HVSMC) and microvascular endothelial cells (HMEC-1) constitutively generate and release vascular endothelial growth factor (VEGF). In contrast, primary macrovascular endothelial cells (HUVEC) produce minute amounts of VEGF. Different statins (atorvastatin, simvastatin and lovastatin, 1-10 micromol/l) significantly reduced basal and cytokine-, nitric oxide- or lysophosphatidylcholine (LPC)-induced VEGF synthesis in HMEC-1 and HVSMC. Interestingly, at the same concentrations statins upregulated VEGF generation in HUVEC. Furthermore, statins exerted dual, concentration-dependent influence on angiogenic activities of HUVEC as determined by tube formation assay. At low concentrations (0.03-1 micromol/l) the pro-angiogenic activity of statins is prevalent, whereas at higher concentrations statins inhibit angiogenesis, despite increasing VEGF synthesis.nnnCONCLUSIONnOur data show that statins exert concentration- and cell type-dependent effects on angiogenic activity of endothelial cells and on VEGF synthesis. The data are of relevance for elucidating the differential activity of statins on angiogenesis in cardiovascular diseases and cancer.

Atorvastatin affects several angiogenic mediators in human endothelial cells.

The pleiotropic effects of statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, have been recently extended to the modulation of angiogenesis. Here, to get more insight into the statins action, the authors have investigated the effect of atorvastatin on the expression of several angiogenic and inflammatory genes in human umbilical endothelial cells (HUVECs). Atorvastatin was proangiogenic at the dose of 10 nM, and antiangiogenic at the concentrations of 1 to 10 micro M. Moreover, these higher concentrations inhibited also the proliferation of HUVECs induced by vascular endothelial growth factor (VEGF). Lower doses of atorvastatin did not influence endothelial cell proliferation. Importantly, atorvastatin at the micromolar concentrations diminished the production of interleukin (IL)-8, a proinflammatory and proangiogenic chemokine, and inhibited the synthesis of urokinase plasminogen activator (uPA), a potent proinflammatory mediator. However, it decreased also the expression of plasminogen activator inhibitor-1 (PAI-1) and thrombospondin-1 (TSP-1), the inhibitors of angiogenesis. Atorvastatin stimulated the expression of angiopoietin (Ang)-2 and moderately enhanced the expression of endothelial nitric oxide synthase (eNOS), whereas heme oxygenase-1 (HO-1) was not significantly affected. In conclusion, the present findings points to other angiogenesis-related effects of atorvastatin, which may be of relevance to the beneficial influence of statins in cardiovascular system.

Morphologic rather than functional or mechanical sonographic parameters of the brachial artery are related to angiographically evident coronary atherosclerosis

OBJECTIVESnThe purpose of this study was to determine the relationship among coronary atherosclerosis and functional, morphologic, and mechanical parameters assessed noninvasively within the brachial artery (BA).nnnBACKGROUNDnFlow-mediated vasodilation (FMD) of the BA, intima-media thickness (IMT) of the carotid artery, and distensibility of the aorta have been correlated with the presence of coronary artery disease (CAD).nnnMETHODSnThe BA was examined with high-resolution ultrasound (13 MHz) in 117 male patients, in whom coronary angiography was performed. Coronary artery disease (> or =30% diameter stenosis in > or =1 major branch) was found in 84 patients, and 33 patients had smooth coronary arteries (non-CAD). Wall cross-sectional area (WCSA) was calculated from resting diameter and IMT.nnnRESULTSnThe BA-WCSA (5.3 +/- 1.5 mm(2) vs. 4.4 +/- 1.4 mm(2), p = 0.002) and IMT (0.37 +/- 0.07 mm vs. 0.31 +/- 0.07 mm, p < 0.001) were significantly greater in patients with CAD compared with non-CAD patients. Flow-mediated vasodilation and distensibility were similar among groups. Using logistic regression analyses adjusting for age, positive family history, hypertension, hypercholesterolemia, smoking, FMD, and distensibility, only WCSA (p < 0.01) and IMT (p < 0.001) correlated independently with the presence of CAD.nnnCONCLUSIONSnMorphologic but not functional and mechanical parameters of the BA are associated with the presence of CAD. Among BA sonographic parameters, IMT and WCSA seem to be the most accurate ones for the estimation of coronary atherosclerotic risk.

Atorvastatin decreases vascular endothelial growth factor in patients with coronary artery disease.

OBJECTIVESnThe aim of this study was to test a possible influence of atorvastatin on the production of vascular endothelial growth factor (VEGF) in patients with coronary artery disease (CAD) and in vitro.nnnBACKGROUNDnVascular endothelial growth factor is suggested to be involved in the growth of atherosclerotic plaque by inducing its neovascularization. Hepatic hydroxymethyl glutaryl-coenzyme A reductase inhibitors (statins) are known to have atheroprotective effects beyond lipid lowering.nnnMETHODSnBlood was collected from 14 male hypercholesterolemic patients with angiographically confirmed CAD at baseline and after two months of atorvastatin therapy (20 mg/d) and from eight male control patients. In an ex vivo assay, human coronary artery smooth muscle cells (HCASMC) were incubated with the patient plasma collected before and after atorvastatin therapy. To test the direct effect of atorvastatin on VEGF synthesis in vitro, HCASMC were treated with atorvastatin (1, 3 and 10 microM). The VEGF concentration was measured by enzyme-linked immunosorbent assay.nnnRESULTSnAtorvastatin therapy reduced VEGF plasma levels in CAD patients (from 31.1 +/- 6.1 to 19.0 +/- 3.6 pg/ml; p < 0.05). The VEGF plasma concentration tended to be higher in CAD patients before treatment compared to control patients (31.1 +/- 6.1 vs. 23.4 +/- 3.6 pg/ml; p = NS). Plasma collected before therapy induced significantly more VEGF in HCASMC compared to the plasma collected after treatment and compared to control cells. In vitro, atorvastatin decreased both the basal and the interleukin-1beta-induced VEGF release in HCASMC.nnnCONCLUSIONSnThese data suggest that atorvastatin may lower the plasma level of VEGF in CAD patients, which could represent a novel beneficial effect of this and perhaps other statins.

Association of wall thickness of the brachial artery measured with high-resolution ultrasound with risk factors and coronary artery disease

Intima-media thickness of the carotid and femoral arteries has been associated with coronary atherosclerosis and its clinical sequelae. The brachial artery (BA) is widely used for the assessment of flow-mediated vasodilation. The aim of this study was to examine whether BA wall thickness (WT) is associated with coronary artery disease (CAD) and risk factors. High-resolution ultrasound (13 MHz) examination of the BA was performed in 179 patients undergoing coronary angiography for the evaluation of chest pain. CAD (> or =30% diameter stenosis in > or =1 major branch) was found in 132 patients, whereas 47 patients had smooth coronary arteries. WT of the posterior BA wall (0.4 +/- 0.05 vs 0.35 +/- 0.06 mm, p <0.001) and wall index (WI) (WT/vessel diameter x 100; 16.1 +/- 0.0 vs 13.8 +/- 0.8, p <0.001) were greater in patients with than without CAD. On univariate analysis, WT and WI correlated with age, presence of CAD, systemic hypertension, maximum coronary diameter stenosis, and baseline diameter. On logistic regression analyses adjusting for age, cholesterol levels, systemic hypertension, smoking, and positive family history, WT (p <0.01) and WI (p = 0.02) remained significantly correlated with the presence of CAD. Thus, BA-WT is independently correlated with the presence of CAD. WT may provide a novel noninvasive marker of atherosclerosis that can be assessed together with flow-mediated vasodilation to yield functional and morphologic information in the same vessel.

Vascular endothelial growth factor (VEGF) plasma concentrations in coronary artery disease

Vascular endothelial growth factor (VEGF) has been associated with atherosclerosis progression and lesion destabilisation. Despite a beneficial effect of local VEGF administration in myocardial and peripheral ischaemia,1 recent evidence suggests a pro-atherosclerotic role of VEGF2 through its ability to enhance plaque inflammatory infiltration and neovascularisation.nnDespite these results, coming mostly from animal studies, there have been few investigations on the relation between VEGF and human coronary artery disease (CAD). These studies yielded conflicting results regarding VEGF concentrations and gene expression in CAD patients compared to controls.3,4 To elucidate the association of VEGF and CAD further, we performed a prospective study in consecutive patients with chest pain undergoing coronary angiography to compare the coronary status with VEGF plasma concentrations.nnWritten informed consent was obtained from 178 patients. Plasma was collected from a femoral artery access immediately before diagnostic coronary angiography. Exclusion criteria were prior myocardial infarction (< 1 month before inclusion), tumour disease, peripheral arterial occlusive disease, ejection fraction < 30%, acute infections, chronic rheumatoid diseases, and chronic obstructive pulmonary disease. Prior statin use was defined as statin treatment for more than 10 days. VEGF plasma concentrations were determined by enzyme linked immunosorbent assay (ELISA, R&D System, Abingdon, UK).nnCoronary angiograms were scored visually by a blinded observer: a severity score (0–3) defined the number of vessels with a luminal stenosis ⩾ 50% (for right, left anterior descending, and …

Chronic heart failure is associated with vascular remodeling of the brachial artery.

Endothelial dysfunction has been shown to correlate with severity of congestive heart failure (CHF) and recent data suggest morphological changes of peripheral vasculature to be associated with the syndrome. We therefore investigated the hypothesis that vascular remodeling is associated with functional changes in peripheral conduit arteries and with systemic overexpression of ET‐1 in patients suffering from CHF.

Vascular endothelial growth factor: angiogenesis, atherogenesis or both?

Vascular endothelial growth factor (VEGF), a specific mitogen for endothelial cells, was initially regarded to be a remedy for impaired reendothelialization of arteries in patients treated with balloon angioplasty. Supplementation with VEGF was also expected to induce the formation of blood vessels

Endothelial Function in a Large Community

To the Editor:nnWe read with interest the study of Benjamin et al1 investigating clinical correlates of flow-mediated vasodilation (FMD) in a large community (The Framingham Heart study) of almost 3000 patients. The authors demonstrated in stepwise multivariable linear regression models that FMD was inversely related to age, systolic blood pressure, body mass index, lipid-lowering medication, and smoking, whereas it was positively associated with female gender, heart rate, and prior walk test. Despite thorough statistical analyses performed in a large cohort, in our opinion some important issues have not been addressed by this study.nnAccording to Figure 2 in the article, the mean FMD% of patients with the lowest risk score was ≈2.8% in men and 4.1% in women, respectively. In an earlier study by the same group,2 mean FMD% in patients with prevalent coronary artery disease (77% men) was 6.7%. Although the discrepancy may be partially explained …