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PDE5 Inhibition Stimulates Tie2-Expressing Monocytes and Angiopoietin-1 Restoring Angiogenic Homeostasis in Diabetes
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PDE5 Inhibition Stimulates Tie2-Expressing Monocytes and Angiopoietin-1 Restoring Angiogenic Homeostasis in Diabetes
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Journal Article
PDE5 Inhibition Stimulates Tie2-Expressing Monocytes and Angiopoietin-1 Restoring Angiogenic Homeostasis in Diabetes
2019
Overview
Abstract
Context
Vascular dysfunction is a common feature in end-organ complications of type 2 diabetes mellitus (T2DM). The endothelium-specific receptor tyrosine kinase Tie2 and its ligand, angiopoietin-1 (Ang1), participate in the processes of vessel repair, renewal, and maturation. However, their dysregulation in T2DM has seldom been investigated.
Objectives
To examine the relationship between angiogenic Tie2-expressing monocytes (TEMs) and Ang1, and their pharmacological modulation by the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, in T2DM and in db/db mouse model.
Design and Setting
Randomized, double-blind, placebo-controlled study.
Patients and Intervention
db/db male mice were randomly assigned to receive 8 weeks of sildenafil or vehicle. Diabetic men were randomly assigned to receive 4 weeks of sildenafil or placebo.
Main Outcomes and Measures
Peripheral blood cells were investigated by flow cytometry to quantify inflammatory myeloid CD11b+ Gr1+ cells and proangiogenic TEMs in mice and classical CD14++CD16neg monocytes and proangiogenic TEMs in humans at baseline and after treatment. In vitro human tube formation assay was used to test serum angiogenic potential.
Results
We show that TEMs and Ang1 are defective in mouse and human models of diabetes and are normalized by PDE5i treatment. Serum angiogenic properties are impaired in diabetes because they do not support the in vitro formation of capillary-like structures, but they are reestablished by in vivo PDE5i treatment.
Conclusions
Restoring a more physiological Tie2-Ang1 axis with sildenafil reestablishes serum angiogenic properties in diabetes, promoting angiogenic homeostasis.
Tie2-expressing monocytes and Ang-1 are novel biomarkers linking chronic inflammation to vascular repair impairment in diabetes; their expression can be modulated by PDE5i.
Publisher
Endocrine Society,Copyright Oxford University Press,Oxford University Press
Subject
/ Analysis
/ Animals
/ Diabetes
/ Diabetes mellitus (non-insulin dependent)
/ Diabetes Mellitus, Type 2 - blood
/ Diabetes Mellitus, Type 2 - drug therapy
/ Diabetes Mellitus, Type 2 - metabolism
/ Ethylenediaminetetraacetic acid
/ Humans
/ Male
/ Mice
/ Neovascularization, Physiologic - drug effects
/ Phosphodiesterase 5 Inhibitors - pharmacology
/ Phosphodiesterase 5 Inhibitors - therapeutic use
/ Placebos - administration & dosage
/ Protein-tyrosine kinase receptors
/ Receptor, TIE-2 - metabolism
/ Sildenafil Citrate - pharmacology
/ Sildenafil Citrate - therapeutic use
/ Tyrosine
