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

Abstract

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 PTP1Bflox/flox mice and subjected to FeCl3 carotid artery injury. Results Genetic deletion of PTP1B in SMCs resulted in adventitia enlargement, perivascular SMA+ and PDGFRβ+ 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 β (TGFβ) signaling components or enzymes involved in extracellular matrix remodeling and TGFβ 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 PDGFRβ 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.

Multi-omics analysis of human tendon adhesion reveals that ACKR1-regulated macrophage migration is involved in regeneration

“…S2B ). MC3 was marked by MYH11 and actin alpha 2, smooth muscle ( ACTA2) and identified as myofibroblasts 23 (Fig. S2B, C ).…”

PTPN1 deficiency modulates BMPR2 signaling and induces endothelial dysfunction in Pulmonary Arterial Hypertension

“…Berdnikovs et al furthermore demonstrated that PTP1B was involved in inflammation as inducible endothelial cell-specific deletion of PTP1B showed a significant increase in accumulation of eosinophils bound to the luminal surface of the endothelium in the lung vasculature and had a decrease in leukocyte recruitment into the lung tissue during ovalbumin-induced allergic lung inflammation[34]. Furthermore, in response to arterial injury, vascular smooth muscle cells deficient for PTPN1 promoted perivascular fibrosis [17]. During respiratory syncytial viral-induced exacerbation of chronic obstructive pulmonary disease, PTPN1 deficiency was shown to promote disease symptoms partly through enhancing S100A9 levels, a damage-associated molecular pattern molecule [35].…”

“…Adenoviral mediated overexpression of dominant negative PTPN1 increased neointima formation in injured rat carotid arteries [16]. Furthermore, following vascular injury, mice deficient to PTPN1 in SMCs developed perivascular fibrosis in carotid arteries[17]. Using hypoxic PASMCs and hypoxia-induced PH mouse models, Freyhaus et al ., demonstrated that hypoxia promoted PDGFRB pathway signaling through inhibiting PTPs, such as SHP-2, TC-PTP, DEP-1, and PTPN1 [18].…”

Multi-omics analysis of human tendon adhesion reveals ACKR1 migrates macrophages involve in endogenous regeneration

“…S2B). MC3 was marked by MYH11 and actin alpha 2, smooth muscle (ACTA2) and identified as myofibroblasts 22 (Fig. S2B, C).…”