Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus

Eric W. Holroyd, Sinny Delacroix, Katarina Larsen, Adriana Harbuzariu, Peter J. Psaltis, Ling Wang, Shuchong Pan, Thomas A. White, Tyra A. Witt, Laurel S. Kleppe, Cheryl S. Mueske, Debabrata Mukhopadhyay, Robert D. Simari

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Objective-Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct. Methods and Results-Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model. Conclusion-These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.

Original languageEnglish (US)
Pages (from-to)704-711
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume32
Issue number3
DOIs
StatePublished - Mar 2012

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Thromboplastin
Endothelial Cells
Vascular Endothelial Growth Factor Receptor-2
Hindlimb
lipoprotein-associated coagulation inhibitor
Peptides
Cell Movement
Ischemia
Phosphorylation

Keywords

  • angiogenesis
  • hemostasis
  • murine models
  • thrombosis
  • tissue factor

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Holroyd, E. W., Delacroix, S., Larsen, K., Harbuzariu, A., Psaltis, P. J., Wang, L., ... Simari, R. D. (2012). Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(3), 704-711. https://doi.org/10.1161/ATVBAHA.111.243733

Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus. / Holroyd, Eric W.; Delacroix, Sinny; Larsen, Katarina; Harbuzariu, Adriana; Psaltis, Peter J.; Wang, Ling; Pan, Shuchong; White, Thomas A.; Witt, Tyra A.; Kleppe, Laurel S.; Mueske, Cheryl S.; Mukhopadhyay, Debabrata; Simari, Robert D.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 32, No. 3, 03.2012, p. 704-711.

Research output: Contribution to journalArticle

Holroyd, EW, Delacroix, S, Larsen, K, Harbuzariu, A, Psaltis, PJ, Wang, L, Pan, S, White, TA, Witt, TA, Kleppe, LS, Mueske, CS, Mukhopadhyay, D & Simari, RD 2012, 'Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus', Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 3, pp. 704-711. https://doi.org/10.1161/ATVBAHA.111.243733
Holroyd, Eric W. ; Delacroix, Sinny ; Larsen, Katarina ; Harbuzariu, Adriana ; Psaltis, Peter J. ; Wang, Ling ; Pan, Shuchong ; White, Thomas A. ; Witt, Tyra A. ; Kleppe, Laurel S. ; Mueske, Cheryl S. ; Mukhopadhyay, Debabrata ; Simari, Robert D. / Tissue factor pathway inhibitor blocks angiogenesis via its carboxyl terminus. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2012 ; Vol. 32, No. 3. pp. 704-711.
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abstract = "Objective-Tissue factor pathway inhibitor (TFPI) is the primary regulator of the tissue factor (TF) coagulation pathway. As such, TFPI may regulate the proangiogenic effects of TF. TFPI may also affect angiogenesis independently of TF, through sequences within its polybasic carboxyl terminus (TFPI C terminus [TFPIct]). We aimed to determine the effects of TFPI on angiogenesis and the role of TFPIct. Methods and Results-Transgenic overexpression of TFPI attenuated angiogenesis in the murine hindlimb ischemia model and an aortic sprout assay. In vitro, TFPI inhibited endothelial cell migration. Peptides within the human TFPIct inhibited endothelial cell cord formation and migration in response to vascular endothelial growth factor (VEGF) 165 but not VEGF121. Furthermore, exposure to human TFPIct inhibited the phosphorylation of VEGF receptor 2 at residue Lys951, a residue known to be critical for endothelial cell migration. Finally, systemic delivery of a murine TFPIct peptide inhibited angiogenesis in the hindlimb model. Conclusion-These data demonstrate an inhibitory role for TFPI in angiogenesis that is, in part, mediated through peptides within its carboxyl terminus. In addition to its known role as a TF antagonist, TFPI, via its carboxyl terminus, may regulate angiogenesis by directly blocking VEGF receptor 2 activation and attenuating the migratory capacity of endothelial cells.",
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AU - Pan, Shuchong

AU - White, Thomas A.

AU - Witt, Tyra A.

AU - Kleppe, Laurel S.

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