Urokinase-derived peptides regulate vascular smooth muscle contraction in vitro and in vivo

Abdullah Haj-Yehia, Taker Nassar, Bruce S. Sachais, Alice Kuo, Khalil Bdeir, Abu Bakr Al-Mehdi, Andrew Mazar, Douglas B. Cines, Abd Al-Roof Higazi

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

We examined the effect of urokinase (uPA) and its fragments on vascular smooth muscle cell contraction. Single-chain uPA inhibits phenylepherine (PE) -induced contraction of rat aortic rings, whereas two-chain uPA exerts the opposite effect. Two independent epitopes mediating these opposing activities were identified. Å6, a capped peptide corresponding to amino acids 136-143 (KPSSPPEE) of uPA, increased the EC50 of PEinduced vascular contraction sevenfold by inhibiting the release of calcium from intracellular stores. A6 activity was abolished by deleting the carboxyl-terminal Glu or by mutating the Ser corresponding to position 138 in uPA to Glu. A single-chain uPA variant lacking amino acids 136-143 did not induce vasorelaxation. A second epitope within the kringle of uPA potentiated PE-induced vasoconstriction. This epitope was exposed when single-chain uPA was converted to a two-chain molecule by plasmin. The isolated uPA kringle augmented vasoconstriction, whereas uPA variant lacking the kringle had no procontractile activity. These studies reveal previously undescribed vasoactive domains within urokinase and its naturally derived fragments.

Original languageEnglish (US)
Pages (from-to)1411-1422
Number of pages12
JournalFASEB Journal
Volume14
Issue number10
DOIs
StatePublished - 2000

Keywords

  • Intracellular calcium
  • Rat aorta
  • Smooth muscle cell
  • Vascular contractility

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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