Abstract Number: OC 38.1
Meeting: ISTH 2022 Congress
Background: Smooth muscle cell (SMC) phenotype switching plays a central role during vascular remodeling. Growth factor receptors are negatively regulated by protein tyrosine phosphatases (PTP), including its prototype PTP1B.
Aims: To 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 cell numbers increased. Elevated mRNA expression of TGFβ signaling components or enzymes involved in extracellular matrix remodeling and TGFβ liberation was seen in injured SMC.PTP1B-KO mouse carotid arteries, and reduced mRNA transcript levels of contractile SMC marker genes were present 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 was reduced. SMAD2 siRNA transfection increased protein levels of PDGFRβ and MYH10 while reducing ERK1/2 phosphorylation, thus phenocopying genetic PTP1B deletion.
Conclusion(s): Chronically reduced PTP1B levels in SMCs promote dedifferentiation, perivascular fibrosis and adverse remodeling following vascular injury by mechanisms involving a ERK1/2 phosphorylation-driven shift from SMAD2 to KLF4 regulated gene transcription.
To cite this abstract in AMA style:Gogiraju R, Gachkar S, Velmeden D, Bochenek M, Zifkos K, Hubert A, Münzel T, Offermanns S, Schäfer K. Protein Tyrosine Phosphatase 1B Deficiency in Vascular Smooth Muscle Cells Promotes Perivascular Fibrosis following Arterial Injury [abstract]. https://abstracts.isth.org/abstract/protein-tyrosine-phosphatase-1b-deficiency-in-vascular-smooth-muscle-cells-promotes-perivascular-fibrosis-following-arterial-injury/. Accessed September 29, 2023.
« Back to ISTH 2022 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/protein-tyrosine-phosphatase-1b-deficiency-in-vascular-smooth-muscle-cells-promotes-perivascular-fibrosis-following-arterial-injury/