Protein-Tyrosine Phosphatases in the Vessel Wall

Abstract

Abstract-Many protein-tyrosine phosphatases (PTPases) have now been identified, but little is known about PTPase expression and regulation in vascular tissue and in vascular disease. Polymerase chain reaction (PCR) amplification and cDNA fingerprinting of PTPase catalytic domains, combined with random sequencing of PCR product libraries, identified 18 (8 receptor-like and 10 cytosolic) PTPases in the rat carotid artery and revealed differential expression of 5 of these PTPases during neointima formation after balloon catheter injury. In situ hybridization was used to localize mRNA expression in vessel cross sections for the 5 differentially expressed PTPases. This revealed that for 3 PTPases (SHP1, CD45, and PTP␤), differential transcript abundance was due to appearance/loss of the cell types by which they were expressed (leukocytes for SHP1 and CD45, endothelial cells for PTP␤). However, mRNA expression of 2 PTPases (PTPL1 and PTP1B) was specifically upregulated by proliferating and migrating smooth muscle cells (SMCs) in characteristic temporal and regional patterns in response to vessel damage. Quantitative PCR analysis showed that PTP1B and PTPL1 were induced Ϸ30-fold and Ϸ60-fold, respectively, by 2 weeks after injury in the damaged vessels compared with the uninjured vessels. PTP1B was rapidly upregulated in the media after vessel injury and remained highly expressed in the developing neointima. By contrast, PTPL1 expression did not increase dramatically until the SMCs had migrated into the intima. The differential expression of PTP1B and PTPL1 by SMCs after injury suggests roles for these PTPases in the regulation of vessel wall remodeling. Key Words: protein-tyrosine phosphatase Ⅲ smooth muscle cells Ⅲ injury Ⅲ neointima Ⅲ carotid arteries A cute arterial injury stimulates smooth muscle cell (SMC) proliferation in the media, followed by the migration of SMCs into the intima. These events result in vessel wall remodeling and the formation of a neointima. Multiple secreted growth factors mediate the SMC proliferation and migration that occurs after balloon catheter injury of the normal rat carotid artery. Basic fibroblast growth factor appears to be the major mitogen driving early medial SMC proliferation, whereas platelet-derived growth factor has a lesser effect on SMC replication but plays a major role in promoting the migration of SMCs into the intima. [1][2][3] Protein-tyrosine phosphatases (PTPases) reverse the activity of growth factor receptor tyrosine kinases and likely play important roles in the vessel wall; however, little is known of the identity of PTPases expressed by vascular tissue, and less is known about the potential roles of specific PTPases in active remodeling. Approximately 70 to 80 PTPases have been cloned and described. 4 The family is broadly divided between receptor-like and cytosolic enzymes and is further divided by the similarities of accessory and regulatory motifs. 5 The receptor PTPases generally contain an extracellular region with adhesion-like motifs, a single membranes...

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