Funmi Belgore

Plasma levels of vascular endothelial growth factor and its soluble receptor (SFlt-1) in essential hypertension.

In this study of 27 untreated patients with uncomplicated essential hypertension, we report on elevated plasma levels of vascular endothelial growth factor and its soluble receptor Flt-1 compared with healthy controls; these increased levels are reduced by the treatment of hypertension. This raises the possibility that abnormal angiogenesis may contribute to the pathogenesis of complications related to hypertension and merits exploration in larger studies.

Endothelial damage and angiogenesis in hypertensive patients: relationship to cardiovascular risk factors and risk factor management*

BACKGROUND Hypertensive patients are at particular risk of cardiovascular complications, possibly related to endothelial damage or dysfunction, or to abnormal angiogenesis. These pathophysiologic processes are assessable by measurement of plasma levels of von Willebrand factor (vWf), and by vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1). We hypothesized that these markers would correlate with the Framingham cardiovascular risk score and would be responsive to treatment. METHODS We measured these markers by enzyme-linked immunosorbent assay in 286 patients with hypertension (239 men; mean age 63 years; mean systolic blood pressure [BP]/diastolic BP 162/89 mm Hg) and additional risk factors, and related them to the patients cardiovascular disease (CVD) and cerebrovascular accident (CVA) risk, using the Framingham equation. Patients were compared with 60 healthy normotensive controls. In 248 patients, the effects of 6 months of intensified cardiovascular risk factor management, including BP and (where appropriate) lipid-lowering treatment, were investigated. RESULTS Plasma VEGF and vWf levels were higher, but sFlt-1 levels lower (all P <.001), in the hypertensive patients compared with the controls. The VEGF and vWf levels correlated significantly with age, systolic and diastolic BP, 10-year CVD risk, and CVA risk scores (all P <.01), whereas sFlt-1 was negatively correlated with these risk scores (P <.01). After intensified cardiovascular risk factor management, total cholesterol, BP, VEGF, and vWf levels were all reduced, yet sFlt-1 levels increased (all P <.05). CONCLUSIONS In hypertension, the processes of endothelial damage and angiogenesis are abnormal, and correlate with overall cardiovascular risk. Indices of endothelial damage and angiogenesis are beneficially changed by intensive cardiovascular risk factor management.

Plasma vascular endothelial growth factor and its receptor Flt-1 in patients with hyperlipidemia and atherosclerosis and the effects of fluvastatin or fenofibrate

Increased vascular endothelial cell growth factor (VEGF) may be important in cardiovascular pathophysiology (perhaps relating to angiogenesis and collateral vessel development) and binds target endothelium via receptors such as Flt-1. We hypothesized that there would be increased levels of plasma VEGF and Flt-1 in patients with atherosclerosis and others with hyperlipidemia compared with controls, and a reduction in these factors with 3 months of lipid-lowering therapy. Twenty patients with uncomplicated hyperlipidemia but no atherosclerosis, 20 patients with hyperlipidemia plus clear atherosclerosis, and 40 matched controls were studied. Plasma VEGF was higher in patient groups than in healthy controls (p <0.01), but Flt-1 was not significantly altered. After lipid-lowering therapy, patients with uncomplicated hyperlipidemia had significantly reduced total cholesterol and VEGF (all p <0.05) but no significant change in Flt-1. Lack of a significant correlation between the von Willebrand factor and VEGF suggests the latter is unrelated to endothelial damage. Plasma VEGF that increases in patients with uncomplicated hyperlipidemia free of major underlying atherosclerosis and in patients with hyperlipidemia plus established atherosclerosis is reduced by successful lipid-lowering treatment. These findings may have implications for the pathophysiology and treatment of hyperlipidemia and atherosclerosis, and suggest an alternative mechanism (i.e., modulation of angiogenesis) by which lipid-lowering therapy may reduce cardiovascular events beyond lipid reduction alone.

Is the Hypercoagulable State in Atrial Fibrillation Mediated by Vascular Endothelial Growth Factor

Background and Purpose— Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state. Methods— We studied 25 patients with AF (20 men; mean±SD age, 62±13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60±9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60±12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay. Results— VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (P <0.001, P =0.022, and P =0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman’s r =0.65, P <0.001) and sFlt (r =0.54, P =0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (r =0.39, P =0.02). There were no significant correlations among the healthy control subjects. Conclusions— Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.

Localisation of members of the vascular endothelial growth factor (VEGF) family and their receptors in human atherosclerotic arteries

Background: Vascular endothelial growth factor (VEGF) mediates endothelial cell mitogenesis and enhances vascular permeability. The existence of single or multiple VEGF isoforms and receptors suggests that these proteins may have overlapping but distinct functions, which may be reflected in their cell expression and distribution. Methods: The localisation of VEGFs A–C and their receptors (VEGFRs 1–3, respectively) in 30 fresh human atherosclerotic arteries, 15 normal uterine arteries, and 15 saphenous veins using immunohistochemistry and western blotting. Results: Saphenous veins showed no staining for VEGF-B or VEGFR-2. Smooth muscle cells (SMCs) showed the strongest staining for VEGF-A, VEGF-B, VEGFR-1, and VEGFR-2 in all specimens. Conversely, VEGFR-3 and VEGF-C were predominately localised to the endothelial vasa vasorum in normal arteries, whereas medial SMCs showed the strongest staining in atherosclerotic arteries. Western blotting showed variations in VEGF protein localisation, with lower amounts of VEGF-B and VEGF-C in saphenous veins, compared with arterial tissue. Amounts of VEGF-C were lower than those of VEGF-A and VEGF-B in all specimens. Conclusion: This study provides direct evidence of the presence of VEGF proteins and receptors in human physiology and pathology, with variations in both the amounts of VEGF proteins expressed and their cellular distribution in normal arteries compared with atherosclerotic arteries. The presence of VEGFs A–C and their receptors in normal arterial tissue implies that VEGF functions may extend beyond endothelial cell proliferation. Reduced VEGFR-2 staining in atherosclerotic arteries may have implications for the atherosclerosis process and the development of vascular disease and its complications.

Plasma levels of vascular endothelial growth factor (VEGF) and its receptor, Flt-1, in haematological cancers : A comparison with breast cancer

Raised plasma VEGF is found in some cancers but levels of its receptor soluble Flt‐1 (sFlt‐1) are unreported. Hypothesising increased levels to be present in haematological cancers, we measured both by ELISA in 22 patients with haematological cancer, 22 with breast cancer, and in age‐ and sex‐matched controls. VEGF was raised in both patients groups compared to controls (P < 0.01) but was higher in haematological cancer compared to breast cancer (P = 0.0238). There was no difference in levels of sFlt‐1. Our data point to changes in levels of plasma VEGF, but not sFlt‐1, in haematological cancer that may have pathophysiological consequences. Am. J. Hematol. 66:59–61, 2001.

Successful therapy reduces levels of vascular endothelial growth factor (VEGF) in patients with hypertension and patients with hypercholesterolemia

We read with interest the paper by Sumino et al. [1], who reported the effect of hormone replacement therapy (HRT) on serum levels of vascular endothelial growth factor (VEGF). They suggested that HRT reduced serum levels of VEGF in normocholesterolemic (NC) postmenopausal women (PMW) with hypertension. Conversely, HRT did not affect VEGF serum levels in the PMW with hypercholesterolemia (HC), of whom 74% were treated hypertensives. We are concerned that their study was based on VEGF measurements in serum samples which has been shown to be inaccurate as this growth factor is released from platelets during clotting [2,3]. Indeed this may explain why some of their observations differed from our recent data. Hypertension and HC are two of the main risk factors for the development of symptomatic atheroselerosis. We have reported raised plasma levels of VEGF in patients with peripheral artery disease and coronary artery disease when compared to healthy normotensive age and sex matched controls [4]. In a pilot study, we also investigated the effects of antihypertensive therapy on VEGF production in 27 untreated patients (15 men, aged 54 years9S.D. 18) with essential hypertension and 27 age and sex matched healthy controls. Plasma VEGF levels in untreated hypertensive patients were significantly higher than levels in healthy normotensive controls (median 130 pg/ml [IQR 10–2025] vs. 75 pg/ml [20–125] Mann–Whitney test, PB0.05). Furthermore, effective antihypertensive therapy lowered blood pressure and significantly reduced median plasma VEGF levels from 130 pg/ml [10–2025] to 60 pg/ml [10–235] after 2 months of therapy (paired Wilcoxon test, PB0.05). Sumino et al. were unable to detect a significant difference at baseline between their study group which was composed of PMW with or without HC and hypertension (66% of the study group), when compared to the control group, which were also not clearly defined and consisted of 60% hypertensives. This may be attributed to the fact that hypertension itself seems to influence VEGF production, and the proposed efficacy in reducing VEGF with HRT in PMW with NC may in fact be a confounding effect of hypertension and/or associated antihypertensive therapy rather than HRT. We have also shown a relationship between plasma VEGF and HC. In a pilot study of 20 patients with total cholesterol of \6.0 mmol/l, and 21 healthy controls, plasma VEGF levels were significantly greater at baseline in patients with HC when compared to controls (median 222 [100–437] vs. 75 [25–11] pg/ml; PB0.05). After 3 months of lipid lowering therapy, median plasma VEGF levels had fallen significantly, to 162 [100–450] pg/ml; PB0.05. In contrast to the study by Sumino et al. [1], we suggest that proper management of HC leads to a reduction in plasma VEGF levels, which may in turn delay or prevent the onset of symptomatic atheroselerosis.