Protein Tyrosine Phosphatase 1B Deficiency in Vascular Smooth Muscle Cells Promotes Perivascular Fibrosis following Arterial Injury

Background Smooth muscle cell (SMC) phenotype switching plays a central role during vascular remodeling. Growth factor receptors are negatively regulated by protein tyrosine phosphatases (PTPs), including its prototype PTP1B. Here, we examine how reduction of PTP1B in SMCs affects the vascular remodeling response to injury. Methods Mice with inducible PTP1B deletion in SMCs (SMC.PTP1B-KO) were generated by crossing mice expressing Cre.ERT2 recombinase under the Myh11 promoter with PTP1B(flox/flox) mice and subjected to FeCl3 carotid artery injury. Results Genetic deletion of PTP1B in SMCs resulted in adventitia enlargement, perivascular SMA(+) and PDGFR beta(+) myofibroblast expansion, and collagen accumulation following vascular injury. Lineage tracing confirmed the appearance of Myh11-Cre reporter cells in the remodeling adventitia, and SCA1(+) CD45(-) vascular progenitor cells increased. Elevated mRNA expression of transforming growth factor beta (TGF beta) signaling components or enzymes involved in extracellular matrix remodeling and TGF beta liberation was seen in injured SMC.PTP1B-KO mouse carotid arteries, and mRNA transcript levels of contractile SMC marker genes were reduced already at baseline. Mechanistically, Cre recombinase (mice) or siRNA (cells)-mediated downregulation of PTP1B or inhibition of ERK1/2 signaling in SMCs resulted in nuclear accumulation of KLF4, a central transcriptional repressor of SMC differentiation, whereas phosphorylation and nuclear translocation of SMAD2 and SMAD3 were reduced. SMAD2 siRNA transfection increased protein levels of PDGFR beta and MYH10 while reducing ERK1/2 phosphorylation, thus phenocopying genetic PTP1B deletion. Conclusion Chronic reduction of PTP1B in SMCs promotes dedifferentiation, perivascular fibrosis, and adverse remodeling following vascular injury by mechanisms involving an ERK1/2 phosphorylation-driven shift from SMAD2 to KLF4-regulated gene transcription.

Automated summary

Reduction of PTP1B in SMCs promotes adverse remodeling following vascular injury, including dedifferentiation, perivascular fibrosis, and collagen accumulation. This process involves a shift from SMAD2 to KLF4-regulated gene transcription driven by ERK1/2 phosphorylation.