Serum Vascular Endothelial Growth factor-A Research Articles

Arterio-venous gradients of IL-6, plasma and serum VEGF and D-dimers in human cancer.

The circulating angiogenic factors vascular endothelial growth factor-A, interleukin-6 and the fibrin D-dimer fragment were measured in the mesenteric vein, the uterine vein, as well as in peripheral venous and arterial samples in 21 randomly selected patients with operable colorectal, ovarian and cervical carcinoma. In addition, immunohistochemistry for vascular endothelial growth factor-A and interleukin-6 was performed on colorectal tumours of such patients. Serum and plasma vascular endothelial growth factor-A were not significantly elevated in the vein draining the tumours, despite tumour cell expression of vascular endothelial growth factor-A. Serum vascular endothelial growth factor-A is therefore not all tumour-derived. In contrast, serum interleukin-6 was highly elevated in the draining veins in agreement with expression of interleukin-6 in the cytoplasm of tumour cells. In the megakaryoblastic cell line MEG-01, the expression of vascular endothelial growth factor-A was found to be regulated by interleukin-6. Thus, the higher platelet vascular endothelial growth factor-A load resulting in higher serum vascular endothelial growth factor levels in cancer patients may partly result from an interleukin-6 mediated up-regulation of the expression of vascular endothelial growth factor-A in the precursor of the platelet, i.e. the megakaryocyte. We also confirmed by immunohistochemistry that platelets adhere and aggregate on tumour endothelium. We propose that interleukin-6 indirectly promotes tumour angiogenesis through its up-regulation of the vascular endothelial growth factor-A load in platelets. In addition, the correlations found between peripheral venous interleukin-6 and peripheral venous fibrinogen and D-dimers levels, and the high D-dimer levels found in the draining vein of the tumour, in agreement with fibrin deposits found in the tumour stroma, suggest an important role for interleukin-6 in extra-vascular fibrinogen metabolism. Our results suggest a pivotal role for interleukin-6 in the intrinsic link between haemostasis and angiogenesis. This might be of importance in the development of anti-angiogenic agents based on interference with haemostasis.British Journal of Cancer (2002) 87, 1437–1444. doi:10.1038/sj.bjc.6600655 www.bjcancer.com© 2002 Cancer Research UK

Elevation of Vascular Endothelial Growth Factor-A Serum Levels Following Acute Myocardial Infarction. Evidence for its Origin and Functional Significance

A. Kranz, C. Rau, M. Kochs and J. Waltenberger. Elevation of Vascular Endothelial Growth Factor-A Serum Levels Following Acute Myocardial Infarction. Evidence for its Origin and Functional Significance. Journal of Molecular and Cellular Cardiology (2000) 32, 65–72. Following the onset of acute myocardial infarction (AMI), a number of serum parameters show well-defined changes reflecting myocardial injury. During the consecutive repair phase, compensatory processes are initiated including the formation of a collateral circulation on the basis of angiogenesis and arteriogenesis. An important angiogenic factor is vascular endothelial growth factor-A (VEGF-A), shown to be upregulated in the ischemic myocardium. It is unclear, however, whether acute myocardial ischemia leads to a detectable elevation of VEGF-A serum concentrations. With the use of an immunoradiometric assay, we measured the levels of VEGF-A in the serum of patients after AMI at defined time intervals, of patients with unstable angina pectoris (UAP) and of healthy individuals. In addition, in a small group of patients with subacute myocardial infarction VEGF-A concentrations were measured in coronary sinus blood. The data are given as median followed by the 25th and 75th percentiles. In the group with AMI serum VEGF-A measured 105 [78; 176] pg/ml on day 1 and 114 pg/ml [72; 163] pg/ml on day 3 after onset of AMI. Serum levels of VEGF-A significantly increased on day 7 after AMI to 189 [119; 373] pg/ml (P=0.0103) and on day 10 to 255 [162; 371] pg/ml (P=0.0007). The VEGF-A serum level in healthy controls and in patients with UAP measured 98 [75; 137] pg/ml and 116 [57; 140] pg/ml, respectively. Serum at day 10 after AMI contained VEGF-A at a biologically relevant concentration capable of stimulating proliferation of endothelial cells. Surprisingly, VEGF-A serum levels were similar in samples taken from the coronary sinus with 61 [43; 83] pg/ml. Therefore the main source for VEGF-A in the blood stream is not the infarcted myocardium. However, the number of platelets, a rich source of VEGF-A, is significantly increased after myocardial infarction, i.e. 284 [252; 363]×109/litre v 220 [177; 250]×109/litre. In conclusion, the time course of VEGF-A elevation following AMI strongly suggests that VEGF-A plays a role as an endogenous activator of coronary collateral formation in the human heart. The most likely source of the elevated VEGF-A are platelets, rather than the infarcted myocardium.