Regulation and Role of Urokinase Plasminogen Activator in Vascular Remodelling

Abstract

1. Urokinase plasminogen activator (uPA) is produced and secreted by multiple vascular cell types, thus influencing the processes and the extent to which the vasculature is remodelled during the development of the intima or a neointima and during hypertrophy and angiogenesis. 2. Urokinase plasminogen activator mRNA expression is up- and down-regulated by growth factors, cytokines and steroids. Urokinase plasminogen activator is secreted as a single chain inactive form that may be proteolytically converted to active or inactive forms. Targeting of proteolytic activity may occur via focalized expression of uPA and its cell surface receptors (uPAR). Proteolytic activity is also controlled through the often co-ordinated expression of specific inhibitors. 3. A proteolytic cascade involving uPA provides its major role in tissue remodelling through the primary degradation of extracellular matrix and secondarily through the activation of transforming growth factor-beta or release from the matrix of basic fibroblast growth factor. In addition, uPA secreted by growth factor-stimulated vascular cells may contribute to the chemotactic and mitogenic responses ascribed to the growth factor and recent evidence strongly suggests that uPA has direct biological actions on vascular cells. 4. The cell surface binding of uPA via its growth factor-like domain to uPAR localizes and activates the protease, but may also initiate transmembrane signalling of biological responses, including migration/invasion and proliferation. As the uPAR lacks intracellular signalling domains, the signals may be transduced via interactions between uPA/uPAR and more classical signalling receptors. The mechanism by which uPA may be involved in cell signalling is yet to be elucidated.

The Chemotactic Action of Urokinase on Smooth Muscle Cells Is Dependent on Its Kringle Domain

“…[1][2][3][4]. Of the two types of plasminogen activators expressed by tissues, urokinase-type plasminogen activator (uPA 1 or urokinase) and tissue-type plasminogen activator (tPA), uPA rather than tPA promotes cell migration (5)(6)(7)(8) and proliferation (9 -11) via interactions with high affinity cell surface receptors (uPAR/CD87).…”

Accelerated plasminogen activator inhibitor may prevent late restenosis after coronary stenting in acute myocardial infarction

“…19 In addition, u-PA and plasmin appear to control vascular remodeling by activation of latent growth factors. 20 Most data evaluating the relationship between PAI-1 plasma levels and restenosis are from balloon angioplasty. The PAI-1 kinetics after coronary stenting and their relationship with the development of in-stent restenosis have not been well documented in either elective or emergent situations.…”

Role of multidomain structure of urokinase in regulation of growth and remodeling of vessels

“…Урокиназа синтезируется эндотелиаль-ными и гладкомышечными клетками сосудов, эпителиальными клетками, фибробластами, моноцитами/макрофагами, а также клетками злокачественных опухолей различного про-исхождения [5][6][7]. В структуре урокиназы выделяют три домена -N-концевой домен, подобный эпидермальному фактору роста, крингл-домен и С-концевой каталитический домен (рис.…”

“…2). Урокиназа секретируется клет-ками в виде одноцепочечного полипептида с молекулярной массой 54 кДа и состоящего из 411 аминокислотных остатков [7]. Одно-цепочечная урокиназа не способна проявлять пептидазную активность в отношении синте-тических субстратов, но при взаимодействии с плазминогеном способна превращать его в…”

“…В настоящее время установлено, что уро-киназа является обязательным участником реакции сосуда на повреждение [7,[134][135][136]. В исследованиях на трансгенных животных [137] и артериях приматов [138] было установлено, что урокиназа является ключевым фактором развития неоинтимы.…”