Aberrant bone marrow vascularization patterns in untreated patients with Gaucher disease type 1.
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.
Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden. Electronic address: monika.klimkowska@karolinska.se.
Monika
M
Klimkowska
Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Maciej
M
Machaczka
Hematology Center Karolinska and Department of Medicine at Huddinge, Karolinska Institute, Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Hematology and Regenerative Medicine, Department of Medicine at Huddinge, Karolinska Institute, Stockholm, Sweden.
Jan
J
Palmblad
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D042682:Angiopoietins / Q000032:analysis; D001853:Bone Marrow / Q000098:blood supply* / Q000473:pathology; D005260:Female; D005776:Gaucher Disease / Q000473:pathology*; D005963:Glucosylceramides / Q000032:analysis; D006801:Humans; D008264:Macrophages / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020286:Pericytes / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D055815:Young Adult
D042682:Angiopoietins; D005963:Glucosylceramides; D042461:Vascular Endothelial Growth Factor A
Angiogenesis; Angiopoietins; Bone marrow; Gaucher disease; Pericytes; VEGF