Pathogenesis of arteriovenous malformations in the absence of endoglin.
BACKGROUND
Arteriovenous malformations (AVMs) result in anomalous direct blood flow between arteries and veins, bypassing the normal capillary bed. Depending on size and location, AVMs may lead to severe clinical effects including systemic cyanosis (pulmonary AVMs), hemorrhagic stroke (cerebral AVMs) and high output cardiac failure (hepatic AVMs). The factors leading to AVM formation are poorly understood, but patients with the familial disease hereditary hemorrhagic telangiectasia (HHT) develop AVMs at high frequency. As most HHT patients have mutations in ENG (endoglin) or ACVRL1 (activin receptor-like kinase 1), a better understanding of the role of these genes in vascular development is likely to reveal the etiology of AVM formation.


OBJECTIVE
Using a mouse with a conditional mutation in the Eng gene, we investigated the sequence of abnormal cellular events occurring during development of an AVM.


RESULTS
In the absence of endoglin, subcutaneous Matrigel implants in adult mice were populated by reduced numbers of new blood vessels compared with controls, and resulted in local venous enlargement (venomegaly). To investigate abnormal vascular responses in more detail, we turned to the more readily accessible vasculature of the neonatal retina. Endoglin-deficient retinas exhibited delayed remodeling of the capillary plexus, increased proliferation of endothelial cells and localized AVMs. Muscularization of the resulting arteriovenous shunts appeared to be a secondary response to increased blood flow.


CONCLUSIONS
AVMs develop when an angiogenic stimulus is combined with endoglin depletion. Moreover, AVM formation appears to result from the combination of delayed vascular remodeling and an inappropriate endothelial cell proliferation response in the absence of endoglin.
Mahmoud
Marwa
M
Institute of Human Genetics, Centre for Life, Newcastle University, NE1 3BZ, United Kingdom.
Allinson
Kathleen R
KR
Zhai
Zhenhua
Z
Oakenfull
Rachael
R
Ghandi
Pranita
P
Adams
Ralf H
RH
Fruttiger
Marcus
M
Arthur
Helen M
HM
D000375:Aging; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D001165:Arteriovenous Malformations / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D015820:Cadherins / Q000235:genetics; D002196:Capillaries / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D019426:Integrases / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D012039:Regional Blood Flow; D015861:Retinal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D000099152:Cadherin 5
D042501:Angiogenic Proteins; D015703:Antigens, CD; D015820:Cadherins; D000071063:Endoglin; D019426:Integrases; D047908:Intracellular Signaling Peptides and Proteins; D000099152:Cadherin 5; C502004:Eng protein, mouse; C045073:Cre recombinase