Unaltered Angiogenesis-Regulating Activities of Platelets in Mild Type 2 Diabetes Mellitus despite a Marked Platelet Hyperreactivity

Abstract

Type 2 diabetes mellitus (T2DM) is associated with platelet dysfunction and impaired angiogenesis. Aim of the study is to investigate if platelet dysfunction might hamper platelet angiogenic activities in T2DM patients. Sixteen T2DM patients and gender/age-matched non-diabetic controls were studied. Flow cytometry and endothelial colony forming cell (ECFC) tube formation on matrigel were used to assess platelet reactivity and angiogenic activity, respectively. Thrombin receptor PAR1-activating peptide (PAR1-AP) induced higher platelet P-selectin expression, and evoked more rapid and intense platelet annexin V binding in T2DM patients, seen as a more rapid increase of annexin V+ platelets (24.3±6.4% vs 12.6±3.8% in control at 2 min) and a higher elevation (30.9±5.1% vs 24.3±3.0% at 8 min). However, PAR1-AP and PAR4-AP induced similar releases of angiogenic regulators from platelets, and both stimuli evoked platelet release of platelet angiogenic regulators to similar extents in T2DM and control subjects. Thus, PAR1-stimulated platelet releasate (PAR1-PR) and PAR4-PR similarly enhanced capillary-like network/tube formation of ECFCs, and the enhancements did not differ between T2DM and control subjects. Direct supplementation of platelets to ECFCs at the ratio of 1:200 enhanced ECFC tube formation even more markedly, leading to approximately 100% increases of the total branch points of ECFC tube formation, for which the enhancements were also similar between patients and controls. In conclusion, platelets from T2DM subjects are hyperreactive. Platelet activation induced by high doses of PAR1-AP, however, results in similar releases of angiogenic regulators in mild T2DM and control subjects. Platelets from T2DM and control subjects also demonstrate similar enhancements on ECFC angiogenic activities.

An optimised protocol for platelet-rich plasma preparation to improve its angiogenic and regenerative properties

“…Controversially, a recent study performed by Miao et al . demonstrated that releasates from PAR-1- or PAR-4-activated platelets from healthy or diabetic patients exert similar levels of endothelial tubular formation in vitro 36 . Differences between the results presented by Miao and those of the current study may be associated with the fact that, while they used WP, we used PRP, adding a possible effect of plasma.…”

Platelet‐rich plasma counteracts detrimental effect of high‐glucose concentrations on mesenchymal stem cells from Bichat fat pad

“…These anomalies lead to hyper‐reactive platelets (Vinik, Erbas, Park, Nolan, & Pittenger, 2001). However, as compared with nondiabetic controls, angiogenic activities of platelets remain unaltered in T2D patients (Miao, Zhang, Huang, & Li, 2016). Some authors have also found that PRP from diabetic patients releases more VEGF and increases proliferation and migration of endothelial cells at larger extent, compared with PRP from healthy donors (Etulain et al, 2018; Karina et al, 2019).…”

Platelet-Cancer Interplay: Molecular Mechanisms and New Therapeutic Avenues

“…Platelet granule release may have anti-angiogenic effects in the tumor microenvironment, because higher endostatin, TSP1, angiostatin levels were measured in serum and urine of different cancer patients ( 57 – 59 ). However, the concept of co-clustering of proteins in distinct granules and differential granule release was challenged by several studies using quantitative enzyme-linked immunosorbent assay (ELISA), confocal immunofluorescence microscopy and proteomic approaches ( 60 – 64 ), which did not observe any functional pattern. Recently, it has been proposed that Stimulated Emission Depletion (STED) imaging can be applied to study platelet granule content and protein clustering in a more precise manner ( 65 , 66 ).…”