Enhanced fetoplacental angiogenesis in pre-gestational diabetes mellitus: the extra growth is exclusively longitudinal and not accompanied by microvascular remodelling

Abstract

Aims/hypothesis. Morphometric studies on pregnancies complicated by gestational diabetes mellitus have found no evidence of increased fetoplacental angiogenesis. Here, placentas from control subjects and patients with pre-gestational Type I (insulin-dependent) diabetes mellitus were used to test for differences in measures of angiogenesis and vascular remodelling. Methods. Term placentas were collected from non-diabetic subjects and well-controlled diabetic patients grouped according to duration and severity into White classes B, C, D and F/R. Tissues were obtained by uniform random sampling for position and orientation. Volumes, surface areas and lengths of peripheral villi and their capillaries were estimated stereologically. Comparisons were drawn by analysis of variance and used to interpret mechanisms of growth, villous capillarization and vessel remodelling. Results. Placentas associated with all classes of diabetes contained greater (19-45%) volumes of fetal capillaries attributable solely to increases in the combined length of capillaries (12-47%) and not to alteration of vessel cross-sectional area or perimeter. Longitudinal growth tended to increase capillarization (capillary:villus length ratios up to 19% larger) but changes were inconsistent between diabetic classes. There was no evidence of altered vascular remodelling (cross-sectional shape factors, perimeter 2 /area, were preserved). Conclusions/interpretations. In well-controlled pre-gestational diabetes, fetoplacental angiogenesis is enhanced and occurs exclusively by longitudinal growth. Differences may involve hypoxic or other metabolic effects on endothelial cells, perivascular cells and angiogenic factors. The findings differ from those previously reported in gestational diabetes. No differences were associated exclusively with the presence of diabetic complications.

A systematic review of placental pathology in maternal diabetes mellitus

“…Several articles included in this systematic review also investigated measures of angiogenesis (31, 35, 41). Two studies adopted the term “redundant capillary connections”, connections that can be removed without disconnecting from the villous capillary bed.…”

“…Jirkovska et al reported increased measures of angiogenesis, determined by an increase in the mean number of redundant connections per terminal villi, in women with GDM (35, 41) and in women with T1DM (35) compared to controls. While another study reported increased measures of fetoplacental angiogenesis, Mayhew et al (31) determined this increase by comparing capillary volume, surface area and length. Mayhew et al (31) characterized these changes in angiogenesis as exclusively longitudinal and not accompanied by any increase in vascular remodeling or changes in capillary caliber.…”

“…While another study reported increased measures of fetoplacental angiogenesis, Mayhew et al (31) determined this increase by comparing capillary volume, surface area and length. Mayhew et al (31) characterized these changes in angiogenesis as exclusively longitudinal and not accompanied by any increase in vascular remodeling or changes in capillary caliber.…”

“…Generally, there are two phases of angiogenesis: (1) branching angiogenesis with formation of tightly looped capillaries and (2) non-branching angiogenesis with formation of longer capillaries (57, 58). One study by Mayhew et al reported increased non-branching angiogenesis, without a change in the cross-sectional caliber or shape of the capillaries, compared to controls in placentas affected with maternal T1DM despite adequate glycated hemoglobin levels (31). Conversely, Jirkovska et al observed increased branching angiogenesis, hypovascular and hypervascular terminal villi, and enhanced capillary surface areas in terminal villi of placentas affected by maternal T1DM with good glycemic control (59).…”

“…Some data suggest similarities, such as increased incidence of placental immaturity (8, 10, 32, 36, 37, 43) and increased angiogenesis (6, 9, 30, 31, 41, 59) compared to normoglycemic pregnancies, and differences in placental findings between women with pregestational diabetes to those with GDM, such as in the thickness of the synctiotrophoblast or basement membrane (50, 51) or severity of placental abnormalities (55). Although it is reasonable to consider that well-controlled diabetes will result in less placental pathology, concomitant maternal conditions are likely to contribute to the placental pathological changes seen in women with diabetes.…”