Servicenavigation

Project Details

Back

Projekt Print View

Protein Tyrosine Phosphatase-1B and vascular signal transduction in obesity

Subject Area Cardiology, Angiology
Endocrinology, Diabetology, Metabolism
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 407333233
 
Final Report Year 2024

Final Report Abstract

The aim of this project was to determine the importance of counterregulatory mechanisms for the signal transduction of vascular cells and the vascular complications in obesity using protein tyrosine phosphatase-1B (PTP1B) as an example. In the first two work packages, we examined whether the expression of PTP1B in endothelial and smooth muscle cells is important for vascular homeostasis and disease. Here, we could show that absence of PTP1B in vascular smooth muscle cells promotes dedifferentiation, perivascular fibrosis, and adverse remodeling following vascular injury by mechanisms involving a shift from SMAD2 to KLF4-regulated gene transcription. Moreover, using mice with inducible deletion of PTP1B in endothelial cells, we could show that absence of PTP1B leads to endothelial activation, increased neutrophil recruitment and ultimately, larger venous thrombi, and that the mechanisms involved elevated SNAP23 phosphorylation and VWF release in the absence of PTP1B. In WP3 and WP4, we examined the role of PTP1B as counterregulator of the neurotrophin receptors, and the influence of obesity and coronary artery disease on the expression of PTP1B and neutrotrophic growth factors in the perivascular adipose tissue. We could show that the expression of BDNF is elevated in PVAT surrounding the proximal aorta (C-PVAT) compared to PVAT surrounding the internal mammary artery (IMA-PVAT), a vessel largely protected from the development of atherosclerosis, independent of obesity, metabolic syndrome, or systemic biomarkers of inflammation. BDNF levels were elevated in parallel with lower TrkB expression and significantly elevated levels of PTP1B, suggesting that vascular BDNF signaling is reduced or lost in patients with coronary atherosclerosis. In vitro, inhibition of PTP1B blunted the effects of BDNF on SMC proliferation, migration, differentiation, and collagen production. To delete PTP1B in vascular smooth muscle cells (SMC.PTP1B-KO), mice expressing Cre.ERT2 recombinase under control of the Myh11 (SMMHC) promoter were crossed with PTP1Bflox/flox mice and subjected to FeCl3 carotid artery injury. The Myh11 promoter is reported to be specific for to mature, differentiated smooth muscle cells (33, 34), however, it turned out that a subpopulation of perivascular progenitor cells also expresses Myh11, and that this subpopulation is relevant during the remodeling response to vascular injury. Genetic fatemapping studies employing Myh11 as Cre driver revealed that differentiated SMCs retain the ability to dedifferentiate and contribute to the vascular progenitor cell pool residing in a niche at the adventitia−media border (35, 36). Our analyses using Myh11 reporter mice extended those previous findings by showing that genetic ablation of PTP1B in Myh11/SMMHC-positive cells increased adventitial SCA1-positive cell numbers following arterial injury. Unexpectedly, chronic deletion of PTP1B in mice was associated with reduced phosphorylation of canonical signaling pathways regulated by PTP1B, such as ERK1/2, probably due to activation of counterregulatory mechanisms in mice with chronic deletion of the phosphatase. It is likely that similar changes in vascular signaling are also present in patients with chronic risk factor exposure and PTP1B inactivation. Konstantinos Zifkos, PhD student in my group and first author of the Circulation Research 2024 publication, was recently awarded the Wissenschaftspreis der Stiftung Mainzer Herz.

Publications

 
 

Additional Information

© 2026 DFG Disclaimer / Copyright / Privacy Policy

Textvergrößerung und Kontrastanpassung