Regulation of Vascular Smooth Muscle Cell Growth by Heparin and Heparan Sulfates

Castellot, John J.; Wright, Thomas C.; Karnovsky, Morris J.

doi:10.1055/s-2007-1003525

Cited by 102 publications

(39 citation statements)

References 64 publications

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“…In this paper we have shown that local controlled release of heparin inhibits SMC proliferation within blood vessels following injury to the endothelium of that blood vessel: for AC heparin without the need for systemic anti-coagulation; for AC heparin when administered from a site distant from the injured vessel; and for some types of heparin in a manner more efficient than in systemic administration. NAC heparin, though equally as effective as the AC heparin at suppressing SMC proliferation in tissue culture (13), was virtually ineffectual when administered i.v. or s.c. and only achieved a therapeutic response when delivered from matrices in the periadventitial position.…”

Section: Discussionmentioning

confidence: 89%

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Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.

Edelman

Adams

Karnovsky

1990

Proc. Natl. Acad. Sci. U.S.A.

212

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Continuous intravenous infusion of heparin suppresses smooth muscle cell proliferation in rats after endothelial injury but may lead to hemorrhage and other complications. The anticoagulant property has been removed from chemically modified heparin without loss of antiproliferative effect but use of such compounds is still limited. In this study ethylene-vinyl acetate copolymer matrices containing standard and modified heparin were placed adjacent to rat carotid arteries at the time of balloon dendothelialization. After 14 days arterial occlusion by smooth muscle cell proliferation was defrmed. Matrix delivery of both heparin compounds effectively diminished this proliferation in comparison to controls without producing systemic anticoagulation or side effects. In addition, this mode of therapy appeared more effective than the administration of the same agents by either intravenous pumps or heparin/polymer matrices placed in a subcutaneous site distant from the injured carotid artery. Thus, heparin's inhibition of smooth muscle cell proliferation after vascular injury might be most effective within the microenvironment of the injured vessel wall, and the accelerated atherosclerosis or restenosis that often follows angioplasty and other vascular interventions might best be treated with site-specific therapy.

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Section: Discussionmentioning

confidence: 89%

“…The different in vivo SMC response from two drugs with identical abilities to inhibit SMC proliferation in tissue culture (13) highlights the complexity of bridging the gap between tissue culture and in vivo systems. Drug absorption, distribution, metabolism, and excretion all affect a compound's biological response after administration.…”

Section: Discussionmentioning

confidence: 99%

Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.

Edelman

Adams

Karnovsky

1990

Proc. Natl. Acad. Sci. U.S.A.

212

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“…43,46 Growth-arrested SMCs in cell culture are 50-100 times more sensitive to the antiproliferative effects of heparin than are exponentially growing cells in culture. 44 Thus, it seems adequate and important to start with LMWH treatment before SMCs are activated by the vessel wall injury caused by PTCA.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.

et al. 1992

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Background. The proliferative response induced by balloon angioplasty is known to be an important factor in the development of restenosis after successful coronary angioplasty.Methods and Results. To study the effects of low-molecular-weight heparin (LMWH) on cellular proliferation after experimental balloon angioplasty, LMWH (3.9 kd, 400 anti-Xa units/kg/day) was given to 20 male New Zealand White rabbits. After an intimal fibromuscular plaque was induced by electrical stimulation in the right carotid artery, LMWH was applied during the 7 days after balloon dilatation. As the control group, 20 other rabbits underwent balloon angioplasty without application of LMWH. The vessels were excised 3, 7, 14, and 28 days after balloon treatment. During the final 18 hours before the rabbits were killed, bromodeoxyuridine was applied. Intimal wall thickness increased from 13±5 cell layers (preangioplasty control group) to 20±6 cell layers in the LMWH-treated group at 28 days (p<0.05). In contrast, histological examination of control animals 28 days after angioplasty revealed a significant increase to 35±+15 cell layers (p<0.01). Immunohistological quantification showed a significant increase (p<0.001) of cells undergoing DNA synthesis at 3 (10.2±4.2%) and 7 (7.7±4.8%) days after balloon dilatation in control animals. In contrast, at 3 and 7 days after balloon treatment, the percentage of cells undergoing DNA synthesis in LMWH-treated rabbits was lower (3 days, 2.7±1.8%; 7 days, 1.9+0.3%) than the corresponding untreated controls but showed a significant increase (p<0.01) compared with the preangioplasty controls. The differences between the two groups were statistically significant, however (3 days, p<0.01; 7 days, p<0.05). As early as 14 days after angioplasty, the extent of

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“…Although most of the actions of heparin on SMC proliferation leads growth arrest (28), heparin possesses multiple functions in EC proliferation; heparin alone inhibits EC proliferation, but potentiates the mitogenic activity of endothelial cell growth factor administered simultaneously (1,2). Heparin stimulates the release of non-PDGF-like endothelial cell-derived growth fac tors from confluently cultured bovine EC (29).…”

Section: Discussionmentioning

confidence: 99%

Heparin Inhibits the Progression Phase of Subcultured Endothelial Cell Proliferation in Rat Aorta

Kimura

Nagaura

Naitoh

et al. 1992

Japanese Journal of Pharmacology

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ABSTRACT-The anti-proliferative effects of heparin on subcultured endothelial cells (EC) of rat aorta were investigated to determine whether heparin inhibits the competence phase or the progression phase in the cell cycle using the starting time and the rate of proliferation. Fetal bovine serum (FBS) stimulated EC proliferation increased to 1.5-times in cell number, but decreased to 0.5-times in 3H-thy midine incorporation, compared with the proliferation of rat primary cultured smooth muscle cells (SMC). The FBS-effects on EC proliferation were attributed to the progression phase rather than the competence phase. Heparin (1, 10 or 100pg/ml) significantly inhibited the proliferation of FBS (5%) stimulated EC, and the extent of inhibition was the same in both cell number and 3H-thymidine incor poration. In the 3H-thymidine incorporation every 3 hr, heparin reduced the rate of incorporation into Go-arrested EC, but did not affect the starting time of DNA synthesis. When the index of competence phase, starting time, was plotted against that of progression phase, rate of proliferation, the inhibition of heparin was attributed to the progression phase. These results demonstrate that heparin selectively inhibits the progression phase in subcultured EC of rat aorta.

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Regulation of Vascular Smooth Muscle Cell Growth by Heparin and Heparan Sulfates

Cited by 102 publications

References 64 publications

Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.

Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury.

Inhibition of cellular proliferation after experimental balloon angioplasty by low-molecular-weight heparin.

Heparin Inhibits the Progression Phase of Subcultured Endothelial Cell Proliferation in Rat Aorta

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