Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Membrane type 1-matrix metalloproteinase (MT1-MMP) has been suggested to play an important role in angiogenesis, but the mechanisms involved remain incompletely understood. Using an in vitro model of angiogenesis in which cell migration of bovine aortic endothelial cells (BAECs) and their morphogenic differentiation into capillary-like structures on Matrigel are induced by overexpression of MT1-MMP, we show that the platelet-derived bioactive lipid sphingosine 1-phosphate (S1P) is the predominant serum factor essential for MT1-MMP-dependent migration and morphogenic differentiation activities. In the presence of S1P, MT1-MMP-dependent cell migration and morphogenic differentiation were inhibited by pertussis toxin, suggesting the involvement of Gi-protein-coupled receptor-mediated signaling. Accordingly, cotransfection of BAECs with MT1-MMP and a constitutively active Galphai2 (Q205L) mutant increased cell migration and morphogenic differentiation, whereas treatment of BAECs overexpressing MT1-MMP with antisense oligonucleotides directed against S1P1 and S1P3, the predominant S1P receptors, significantly inhibited both processes. These results demonstrate that MT1-MMP-induced migration and morphogenic differentiation involve the cooperation of the enzyme with platelet-derived bioactive lipids through S1P-mediated activation of Galphai-coupled S1P1 and S1P3 receptors. Given the important contribution of platelets to tumor angiogenesis, the stimulation of endothelial MT1-MMP function by S1P may thus constitute an important molecular event linking hemostasis to angiogenesis.
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PMID:Membrane type 1-matrix metalloproteinase (MT1-MMP) cooperates with sphingosine 1-phosphate to induce endothelial cell migration and morphogenic differentiation. 1507 Jun 79

Endothelial cells (ECs) are covered by a surface glycocalyx layer that forms part of the barrier and mechanosensing functions of the blood-tissue interface. Removal of albumin in bathing media induces collapse or shedding of the glycocalyx. The electrostatic interaction between arginine residues on albumin, and negatively charged glycosaminoglycans (GAGs) in the glycocalyx have been hypothesized to stabilize the glycocalyx structure. Because albumin is one of the primary carriers of the phospholipid sphingosine-1-phosphate (S1P), we evaluated the alternate hypothesis that S1P, acting via S1P1 receptors, plays the primary role in stabilizing the endothelial glycocalyx. Using confocal microscopy on rat fat-pad ECs, we demonstrated that heparan sulfate (HS), chondroitin sulfate (CS), and ectodomain of syndecan-1 were shed from the endothelial cell surface after removal of plasma protein but were retained in the presence of S1P at concentrations of >100 nM. S1P1 receptor antagonism abolished the protection of the glycocalyx by S1P and plasma proteins. S1P reduced GAGs released after removal of plasma protein. The mechanism of protection from loss of glycocalyx components by S1P-dependent pathways was shown to be suppression of metalloproteinase (MMP) activity. General inhibition of MMPs protected against loss of CS and syndecan-1. Specific inhibition of MMP-9 and MMP-13 protected against CS loss. We conclude that S1P plays a critical role in protecting the glycocalyx via S1P1 and inhibits the protease activity-dependent shedding of CS, HS, and the syndecan-1 ectodomain. Our results provide new insight into the role for S1P in protecting the glycocalyx and maintaining vascular homeostasis.
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PMID:Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. 2428 15