Aberrant bone marrow vascularization patterns in untreated patients with Gaucher disease type 1.

ABSTRACT

Bone marrow (BM) in subjects with Gaucher disease (GD) displays accumulation of Gaucher cells (GC), i.e. glucocerebroside-laden macrophages. Following the assumption that macrophage proliferation and perturbation in GD modulates local inflammation-associated phenomena including angiogenesis, BM biopsies from 11 untreated GD patients and 36 controls were investigated for morphology and angiogenesis-associated features. These included microvascular density, (MVD), vessel structure and pericyte coverage, expression of VEGF-A and angiopoietins (ANGPT1 and 2). In GD BM, cellularity was higher, and GC clustered in cohesive but poorly demarcated areas, leaving irregular islands with normal hematopoiesis. MVD was 2.6-fold higher in GD marrows than in controls (p<0.001). In GC-rich areas, MVD was 1.4-fold higher (p=0.026), and vessel architecture was abnormal compared with GC-poor areas. MVD correlated with BM cellularity, particularly in GC-rich areas. Moreover, 30±17% of GD BM vessels were pericyte-coated, significantly fewer than in controls (48±16%; p<0.001). Expression of ANGPT1 and 2 was significantly higher in GD BM vessel walls than in controls (7.2- and 13.2-fold higher), whereas VEGF expression was 20-fold lower (p<0.05 for all). Thus, human GD BM shows increased angiogenesis with defective pericyte coating and skewed VEGF/ANGPT1 and 2 balances, presumably related to local accumulation of GC.