Placental Gestational Diabetes Mellitus Endothelial Cell- Pericyte Cross talk: A novel approach to examine human Adult Type 2 Diabetic Retinopathy

Abstract

Purpose : Animal models of Diabetic Retinopathy do not recapitulate human disease. We hypothesized that the morphological and functional cross talk between the placental Gestational Diabetes Mellitus (GDM)- endothelial progenitor cell and pericyte is an alternate human model to examine T2DM.

Methods : Fresh placentas were obtained from 15 cases each of GDM and healthy controls. Foetal placental endothelial progenitor cells (EPCs) and pericytes were isolated, characterized and expanded from the placental disc and umbilical cord blood. All placentas were processed for histological examination, light and transmission electron microscopy, gene expression and in vivo transplantation into CB17/Icr-Prkdc^scid/IcrIcoCrl mice. The Mann Whitney test was used for statistical analysis.

Results : Histology showed chorangiosis and increased capillary diameter of blood vessels in the GDM vasculature (p ≤ 0.001). Transmission Electron Microscopy demonstrated pericyte ghosts, increased microvessel density and thickening of capillary basement membranes reminiscent of adult Type 2 Proliferative Diabetic Retinopathy in GDM that was not seen in healthy controls (p ≤ 0.001). Endothelial cell irregularity was noted in 76% GDM vs. 10.4% healthy placentas (p ≤ 0.001). GDM endothelial progenitor cells failed to form tubes on matrigel in vitro (Figure 1). Placental foetal GDM -EPCs and pericytes showed poorly perfused vascular structures in vivo when implanted in subcutaneous matrigel plugs in CB17/Icr-Prkdc^scid/IcrIcoCrl SCID mice, as compared with healthy control placental EPCs and pericytes. Up regulation of angiogenic molecular signatures is noted in blood vessels of GDM vascular progenitor cells (p ≤ 0.001).

Conclusions : We have detected a striking resemblance of placental foetal vascular progenitor cells exposed to short duration hyperglycemia from Gestational Diabetes Mellitus in a cohort from South India that resembles adult Type 2 proliferative diabetic retinal cells. This could point to the role of the intrauterine environment influencing the development of Type 2 Diabetic microvascular disease in adult hood. The GDM placenta is a research tool that would enhance our understanding of pathophysiology and molecular signatures of Adult Type 2 Proliferative Diabetic Retinopathy.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

 

Fetal Gestational Diabetes Mellitus- Endothelial progenitor cells fail to form tubes on matrigel