Background: Perivascular fibrosis, the deposition of extracellular matrix around blood vessels, reduces vascular compliance and impairs blood flow thus contributing to cardiac and vascular dysfunction and disease. Targeting perivascular fibrosis might have therapeutic potential for cardiovascular disease processes. However, the mechanism underlying perivascular fibrosis are incompletely understood.

Aims: To determine the importance of protein tyrosine phosphatase-1B (PTP1B), a negative regulator of tyrosine kinase receptors, for perivascular fibrosis.

Methods: Mice with smooth muscle cell-specific deletion of PTP1B (SMC.PTP1B-KO) were generated by crossing mice transgenic for Cre.ERT2 recombinase under control of the SMMHC promotor with PTP1B flox/flox transgenic mice. Vascular injury and neointima formation was induced in 12-16 week-old male mice at the carotid artery using 10% ferric chloride. For functional and mechanistic analyses in vitro, primary smooth muscle cells were isolated from the aorta of male SMMHC.Cre wild-type mice.

Results: Histochemical analyses revealed that absence of PTP1B in SMMHC-positive cells resulted in a significant increase in the adventitia area (P=0.004) and thickness (P< 0.001) following vascular injury. Moreover, a significant increase in the total number of adventitial cells (P=0.002) and higher numbers of PCNA-positive, proliferating cells (P=0.009) were observed. Histochemical characterization revealed a greater percentage of cells expressing smooth muscle alpha-actin (SMA; P< 0.0001) and platelet-derived growth factor (PDGF) receptor-beta (P=0.004) in the adventitia of SMC.PTP1B-KO mice. Also, larger amounts of interstitial collagen (P=0.012) were observed, whereas the number of cells expressing the pericyte marker NG2 did not differ (P=0.460). In vitro, exposure of murine primary aortic smooth muscle to hypoxia in the presence of a chemical PTP1B inhibitor resulted in increased HIF1alpha and PDGF protein levels.

Conclusions: Our findings suggest that absence of PTP1B in smooth muscle cells may promote adventitia enlargement and perivascular fibrosis under hypoxic stress by increasing the expression of PDGF and subsequent proliferation and differentiation of smooth muscle (progenitor) cells.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/absence-of-protein-tyrosine-phosphatase-1b-in-smooth-muscle-cells-promotes-perivascular-fibrosis-role-of-receptor-tyrosine-kinase-signaling/