Venous Intimal Hyperplasia Research Articles

Recombinant mitotoxin basic fibroblast growth factor-saporin reduces venous anastomotic intimal hyperplasia in the arteriovenous graft.

The plant cytotoxin saporin (SAP) is a potent ribosome-inactivating protein. When conjugated to basic fibroblast growth factor (FGF2), it selectively kills proliferating cells that have upregulated FGF receptors. In this study, we evaluated the effect of the recombinant chimeric mitotoxin rFGF2-SAP on venous anastomotic intimal hyperplasia, a major cause of failure of arteriovenous (AV) grafts. Recently designed expanded polytet-rafluoroethylene-based local infusion devices were implanted bilaterally as femoral AV conduits in six dogs. The venous anastomoses were the sites of continuous delivery of rFGF2-SAP (2.7 micrograms.kg-1.d-1) to one side and vehicle (4.6 microL.kg-1.d-1) as control to the contralateral side for 14 days. All animals survived, and all grafts were patent. Liver enzyme levels and histological analyses of liver, kidneys, and brain were normal, indicating the absence of systemic toxicity. Morphometric measurements and measurements of cell proliferation by bromodeoxyuridine index analysis were performed at both arterial and venous anastomoses. There were no significant differences between the treated grafts and the control grafts in intimal hyperplasia and intimal cell proliferation at the arterial anastomoses. In contrast, rFGF2-SAP reduced intimal thickness by 32%, intimal area by 40%, and cell proliferation index by 33% at the treated venous anastomoses compared with the control venous anastomoses (P < .05). These data demonstrate that local infusion of rFGF2-SAP significantly reduces venous anastomotic intimal hyperplasia and cell proliferation without systemic toxicity. This study suggests a new strategy for reducing intimal hyperplasia by the selective killing of proliferating smooth muscle cells with a potent chimeric mitotoxin through a novel local infusion device.

Autoradiographic mapping and characterization of insulin-like growth factor-I receptor binding in human greater saphenous vein

Purpose: The proliferation of vascular smooth muscle cells is an important step in the process of intimal hyperplasia. Veins exposed to arterial pressure develop intimal hyperplastic lesions that lead to failure of vein bypasses. Insulin-like growth factor-I is a polypeptide hormone structurally related to insulin with insulin-like metabolic effects. Insulin-like growth factor-I has been found to work in concert with other growth factors, including platelet-derived growth factor, to promote the growth of vascular smooth muscle cells in culture. Insulin-like growth factor-I exerts its effects via specific receptors located on the cell surface. We studied the in situ distribution of insulin-like growth factor-I receptor binding using autoradiography and examined insulin-like growth factor-I binding characteristics in normal human greater saphenous vein.Methods: Frozen sections 20 μm thick were prepared from the greater saphenous vein specimens. The sections were incubated in a buffer containing 125I-insulin-like growth factor-I in the presence of increasing concentrations of the unlabeled peptide. Autoradiograms were obtained by apposing the treated sections to autoradiography film.Results: Analysis of the autoradiographs showed that insulin-like growth factor-I binding was consistently present in the wall of human greater saphenous vein. To characterize these binding sites binding inhibition studies were performed. High-affinity insulin-like growth factor-I receptor binding was found with dissociation constant of 1.0 ± 0.32 nmol/L and maximum binding capacity of 0.46 ± 0.23 pmol/mg protein. These values are consistent with a physiologic role for insulin-like growth factor-I in the tissue examined.Conclusions: The presence of high-affinity (dissociation constant = 1.0 ± 0.32) insulin-like growth factor-I binding sites in the wall of saphenous vein suggests that insulin-like growth factor-I plays an important role in regulating the proliferation of venous wall cellular components, an essential step in the process of venous intimal hyperplasia.

Ultrasonic tissue characterization of experimental venous intimal hyperplasia.

Ultrasonic tissue characterization (UTC) employing slope and Y-intercept parameters from the normalized power spectrum of backscattered echoes was employed in vivo to study compositional changes in the walls of pig jugular veins in which thrombi were experimentally induced. Light microscopy revealed these changes to be intimal hyperplasia with an early predominance of smooth muscle cells and a later mixture of smooth muscle cells and collagen deposits. UTC distinguished intimal hyperplasia from previously reported data from luminal thrombosis UTC. Furthermore, UTC was able to discriminate between early (predominantly smooth muscle cells) and older (smooth muscle cells plus collagen deposits) intimal hyperplasia. The study suggests that intimal hyperplasia in the experimental model used may be organized thrombus and that UTC may be able to follow both the development of wall changes as well as luminal changes occurring in venous thrombosis.

Responsiveness of vein bypass grafts to stimulation with norepinephrine and 5-hydroxytryptamine.

The in vitro reactivity of vein bypass grafts to norepinephrine (NE) and 5-hydroxytryptamine (5-HT) was studied in 20 rabbits undergoing bypass grafting. In these animals the right external jugular vein was grafted into the right carotid artery. The cumulative dose-response to NE and 5-HT of rings of vein grafts 2, 4, and 6 weeks after insertion was compared with that of rings from the normal contralateral jugular vein by means of an organ bath to measure changes in isometric tension. With NE there was no significant difference in the response of vein grafts harvested at 2 weeks and control veins. However, at 4 and 6 weeks there was a progressive decrease in the sensitivity of the grafts to NE. The difference in ED50 values (ED50 defined as concentration of agonist required to elicit 50% of the maximal response) between control veins and vein grafts at 4 weeks was twofold and at 6 weeks it was fivefold. None of the control veins responded to 5-HT stimulation. However, the vein grafts contracted with 5-HT, exhibiting sigmoid dose-response curves. The vein grafts showed intimal hyperplasia, which was maximal after 4 weeks. These results show that vein grafts undergo a progressive decrease in their sensitivity to norepinephrine and develop a marked, sustained increase in sensitivity to 5-HT. This finding is in contrast to previous observations in intimal hyperplastic rabbit aorta, suggesting a fundamental difference in the functional expression of arterial and venous intimal hyperplasia.