Histological morphology related to angiogenesis and hypoxia in congenital vascular malformations : exploring aetio-pathology and future target therapy
Author(s)
Maftei, Nonica
Type
Thesis
Abstract
Background
Musculoskeletal arteriovenous malformations (AVMs) result from abnormal angiogenesis and belong to congenital vascular malformations (CVMs) group. AVMs persist and have associated morbidity and even mortality. The aetio-pathogenesis of AVMs is unknown. This study analyses histological morphology and the immunohistological expression of specific angiogenesis and hypoxia markers in comparison with control tissues in patients with CVMs. CVM pO2 was further assessed. This work was performed to gain insight into possible mechanisms involved in aetio-pathogenesis of CVMs.
Methods
Thirty three consecutive CVMs and 10 control specimens were analysed morphologically using routine techniques, histochemical (H&E, Masson Trichrome, Elasic Von Gieson, Toluidine blue) and immunohistochemical (CD68, CD3, CD20, Factor VIII, actin 1-α, ki67 and S100). Further immunohistochemical studies analysed VEGF A, VEGFR-1, Tie-2, αV3 and αV5 integrins, HIF-1α and HIF-2α, CAIX. The neutral endopeptidase (NEP) was studied by immunostaining for CD10 on 38 CVMs. Intraoperative blood samples from CVMs were analysed for pO2.
Results
Macrophages (p<0.0001), mast cells (p<0.0001), vessel number (p=0.0004) and diameters (p=0.0005) were significantly higher in the CVMs compared to controls. The expression of all angiogenesis markers were significantly higher in CVMs comparing to controls. HIF-1α, HIF-2α and CD10 (p=0.0002) were over-expressed in CVMs. There was a positive correlation between HIF-2α expression and VEGF A (p=0.0001), VEGFR-1 (p=0.0043), Tie-2 (p=0.03), αVβ3 (p=0.029), αVβ5 (0.045), CD10 (p=0.0002) and inflammatory cells in CVMs. Comparisons of CVM and arterial blood pO2 were not significant (p=1).
Discussion
Inflammation and imbalance of angiogenic and hypoxia markers are implicated in CVM pathogenesis. HIF-2α may play a more important role in CVM pathgogenesis than HIF-1α. CVM blood has an arterial pattern in spite of expressing HIF. CD10 may be a potential marker for CVMs in biopsies. Molecular patterns and potential signalling pathways involved in CVM pathogenesis are implicated in this work. This enhanced clinico-pathological correlation should improve therapeutic options and efficacy.
Musculoskeletal arteriovenous malformations (AVMs) result from abnormal angiogenesis and belong to congenital vascular malformations (CVMs) group. AVMs persist and have associated morbidity and even mortality. The aetio-pathogenesis of AVMs is unknown. This study analyses histological morphology and the immunohistological expression of specific angiogenesis and hypoxia markers in comparison with control tissues in patients with CVMs. CVM pO2 was further assessed. This work was performed to gain insight into possible mechanisms involved in aetio-pathogenesis of CVMs.
Methods
Thirty three consecutive CVMs and 10 control specimens were analysed morphologically using routine techniques, histochemical (H&E, Masson Trichrome, Elasic Von Gieson, Toluidine blue) and immunohistochemical (CD68, CD3, CD20, Factor VIII, actin 1-α, ki67 and S100). Further immunohistochemical studies analysed VEGF A, VEGFR-1, Tie-2, αV3 and αV5 integrins, HIF-1α and HIF-2α, CAIX. The neutral endopeptidase (NEP) was studied by immunostaining for CD10 on 38 CVMs. Intraoperative blood samples from CVMs were analysed for pO2.
Results
Macrophages (p<0.0001), mast cells (p<0.0001), vessel number (p=0.0004) and diameters (p=0.0005) were significantly higher in the CVMs compared to controls. The expression of all angiogenesis markers were significantly higher in CVMs comparing to controls. HIF-1α, HIF-2α and CD10 (p=0.0002) were over-expressed in CVMs. There was a positive correlation between HIF-2α expression and VEGF A (p=0.0001), VEGFR-1 (p=0.0043), Tie-2 (p=0.03), αVβ3 (p=0.029), αVβ5 (0.045), CD10 (p=0.0002) and inflammatory cells in CVMs. Comparisons of CVM and arterial blood pO2 were not significant (p=1).
Discussion
Inflammation and imbalance of angiogenic and hypoxia markers are implicated in CVM pathogenesis. HIF-2α may play a more important role in CVM pathgogenesis than HIF-1α. CVM blood has an arterial pattern in spite of expressing HIF. CD10 may be a potential marker for CVMs in biopsies. Molecular patterns and potential signalling pathways involved in CVM pathogenesis are implicated in this work. This enhanced clinico-pathological correlation should improve therapeutic options and efficacy.
Date Issued
2012
Date Awarded
2013-01
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Standfield, Nigel
Publisher Department
Surgery and Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Medicine (Research) MD (Res)