Abnormal nonstoring capillary endothelium: a novel feature of Gaucher disease. Ultrastructural study of dermal capillaries

Abstract

Ultrastructural study of skin biopsies in two cases of Gaucher disease (GD) patients (types II and III) revealed hitherto unknown alteration of the blood capillary endothelial cells (ECs) featured by hypertrophy and numerous subplasmalemmal microvesicles underneath both the apical and basal membranes. There was also prominent apical membrane folding with formation of filiform and large cytoplasmic projections, with occasional transcapillary cytoplasmic bridges. Similar, though less frequently expressed, changes were manifested at the basal membrane by numerous cytoplasmic projections into the subendothelial space. Regressive changes with EC breakdown were rare. Lysosomal storage was always absent. Besides EC hypertrophy, there was also increased EC density in the capillary lumen, leading to pronounced changes in capillary architecture with loose or incomplete EC anchoring. There were also signs of EC sprouting. Some pericytes displayed an increase in size and number of cytoplasmic processes, which often extended into distant pericapillary regions. The spectrum of changes suggests that a significant positive growth effect on EC occurs in GD. The putative mechanisms triggered by GBA1 deficiency leading to EC involvement are discussed. The authors are well aware of the fact the results, based on a nontraditional type of bioptic samples, are preliminary, but they are worth following, as further ultrastructural and functional studies of blood endothelium in GD may open a novel field in molecular cell pathophysiology of the disorder: endothelial dysfunction.

Fig. 1

a Dermal capillary (case 2) showing numerous enlarged endothelial cells (ECs) with prominent folding of both the apical and basal pole membranes. b Dermal capillary (case 2) showing enlarged, irregular ECs with uneven apical pole membranes. One of them can be seen to be loosely anchored. Li lipopigment deposits. c Dermal capillary (case 1) showing enlarged ECs with prominent folding at the basal pole and limited by a multilayered basement membrane. ECs display loose intercellular connections. The apical part of the EC at the center protrudes prominently into the capillary lumen. d Dermal capillary (case 2) with an obliterated lumen caused by enlarged ECs. Note the prominent folding of the apical membranes and fusion between opposite ECs. Note also the loose intercellular connections

Fig. 2

a Dermal capillary (case 2) showing discontinuous endothelial cells (ECs) displaying loose anchoring and formation of a second endothelial layer. b Dermal capillary (case 1) with an enlarged single EC. A prominently activated apical pole forms a transluminal bridge (arrows). Note the large pericyte on the left. c Dermal capillary (case 2) with the lumen almost completely obliterated by the enlarged, folded EC cytoplasm. Note the cytoplasmic transformation into a dense mesh and the numerous Weibel-Pallade granules. The thin basement membrane is almost invisible on the left side. d Dermal capillary (case 2) showing details of EC apical membrane folding together with numerous ribosomes and occasional microvesicles

Fig. 3

a Dermal capillary (case 1) showing a level of degeneration approaching cytoplasmic lysis (asterisks). b Dermal capillary (case 2) showing endothelial-cell (EC) hypertrophy and numerous surrounding pericytes. Note that one of the pericytes (P) is some distance from the capillary and completely detached but still expresses a pericellular membrane and subplasmalemmal microvesicles around its entire perimeter. c Dermis (case 1) showing structures compatible with EC sprouting. There is a single EC (EC) with three cytoplasmic extensions, one of them definitely luminized (Lu). d Branched dermal capillary (case 1). Note the large lumen at the right lined with very thin EC cytoplasm. On the left are three enlarged ECs, which are prominently protruding into the obliterated lumen. The architectural pattern is compatible with intussusceptive-type angiogenesis

Fig. 4

Comparative group of skin biopsies showing variability of capillary endothelial cell (EC) appearance. a Flat EC, a frequent finding. b, c Larger EC with rudimentary folding of the apical membrane. d Enlarged EC with smooth membranes at both apical and basal poles