Heparin Inhibition of Endothelial Cell Proliferation and Organization is Dependent on Molecular Weight

Alok A. Khorana, Abha Sahni, Owen D. Altland, Charles W. Francis

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Objective - Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in Mr on selected endothelial cell properties. Methods and Results - Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in M r. Cell proliferation was assessed by [3H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94±2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58±8%) or 3-kDa LMWH (60±9%, P=0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three- and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58±15% and 67±9% (P<0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. Conclusions - Heparin inhibition of endothelial cell proliferation and organization requires a chain length of >8 saccharide units, with maximal inhibition at Mr of 6 kDa. This Mr dependence differs from that required for anticoagulant activity.

Original languageEnglish (US)
Pages (from-to)2110-2115
Number of pages6
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume23
Issue number11
DOIs
StatePublished - Nov 2003
Externally publishedYes

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Heparin
Endothelial Cells
Molecular Weight
Cell Proliferation
Low Molecular Weight Heparin
Human Umbilical Vein Endothelial Cells
Fibroblast Growth Factor 2
Anticoagulants
Thymidine
Blood Vessels
Neoplasms
Survival
Growth

Keywords

  • Angiogenesis
  • Cancer
  • Endothelium
  • Low molecular weight heparins
  • Thrombosis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Heparin Inhibition of Endothelial Cell Proliferation and Organization is Dependent on Molecular Weight. / Khorana, Alok A.; Sahni, Abha; Altland, Owen D.; Francis, Charles W.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 23, No. 11, 11.2003, p. 2110-2115.

Research output: Contribution to journalArticle

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AB - Objective - Studies have shown improved survival in cancer patients treated with low molecular weight heparins (LMWHs). Tumors depend on an expanding vasculature, and heparins may affect vessel growth and function. We investigated the effect of heparins differing in Mr on selected endothelial cell properties. Methods and Results - Human umbilical vein endothelial cells were cultured with fibroblast growth factor-2 and heparins differing in M r. Cell proliferation was assessed by [3H]thymidine incorporation, and vascular organization was assessed by in vitro assays. Maximum inhibition of 94±2% was observed with 6-kDa LMWH, greater than the inhibition seen with unfractionated heparin (58±8%) or 3-kDa LMWH (60±9%, P=0.02 for both). No inhibition of proliferation was observed with heparin tetrasaccharide, octasaccharide, or pentasaccharide (fondaparinux). Three- and 6-kDa fractions decreased endothelial tube formation in Matrigel to 58±15% and 67±9% (P<0.05), respectively, of that with fibroblast growth factor-2, whereas no inhibition was observed with unfractionated heparin, tetrasaccharide, pentasaccharide, or octasaccharide. LMWH (6 kDa) also inhibited vessel formation in a placental explant. Conclusions - Heparin inhibition of endothelial cell proliferation and organization requires a chain length of >8 saccharide units, with maximal inhibition at Mr of 6 kDa. This Mr dependence differs from that required for anticoagulant activity.

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