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,1,**,2
* School of Pharmacy and the
Department of Clinical Biochemistry, Hebrew University-Hadassah Medical Centers, Jerusalem, Israel IL-91120;
Departments of Pathology and Laboratory Medicine,
§ Environmental Medicine and
** Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA; and the
Department of Biology, Angstrom Pharmaceuticals Inc., San Diego California 92121, USA
2Correspondence: University of Pennsylvania, Dept. Pathology and Laboratory Medicine, 513A Stellar-Chance, 422 Curie Blvd., Philadelphia, PA 19104, USA. E-mail: higazi{at}mail.med.upenn.edu
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 PE-induced vascular contraction sevenfold by inhibiting the release of calcium from intracellular stores. Å6 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.—Haj-Yehia, A., Nassar, T., Sachais, B. S., Kuo, A., Bdeir, K., Al-Mehdi, A. B., Mazar, A., Cines, D. B., Higazi, A. A. Urokinase-derived peptides regulate vascular smooth muscle contraction in vitro and in vivo.
Key Words: smooth muscle cell • intracellular calcium • vascular contractility • rat aorta
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