Endoglin Expression Is Reduced in Normal Vessels but Still Detectable in Arteriovenous Malformations of Patients with Hereditary Hemorrhagic Telangiectasia Type 1

Abstract

Endoglin is predominantly expressed on endothelium and is mutated in hereditary hemorrhagic telangiectasia (HHT) type 1 (HHT1). We report the analysis of endoglin in tissues of a newborn (family 2), who died of a cerebral arteriovenous malformation (CAVM), and in a lung specimen surgically resected from a 78-year-old patient (family 5), with a pulmonary AVM (PAVM). The clinically affected father of the newborn revealed a novel mutation that was absent in his parents and was identified as a duplication of exons 3 to 8, by quantitative multiplex polymerase chain reaction. The corresponding mutant protein (116-kd monomer) and the missense mutant protein (80-kd monomer) present in family 5 were detected only as transient intracellular species and were unreactive by Western blot analysis and immunostaining. Normal endoglin (90-kd monomer) was reduced by 50% on peripheral blood-activated monocytes of the HHT1 patients. When analyzed by immunostaining and densitometry, presumed normal blood vessels of the newborn lung and brain and vessels adjacent to the adult PAVM showed a 50% reduction in the endoglin/PECAM-1 ratio. A similar ratio was observed in the CAVM and PAVM, suggesting that all blood vessels of HHT1 patients express reduced endoglin in situ and that AVMs are not attributed to a focal loss of endoglin.

Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

“…A decrease in either TGF-␤1 or TGF-␤1 receptors can lead to unstable cellular interactions in the vessel wall, dilated vessels, and vascular abnormalities. Such alterations could damage other angiogenic regulatory mechanisms and lead to deterioration of the vascular network associated with the progression of HHT (Bourdeau et al, 2000).…”

Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment

“…The somewhat simplistic concept of a somatic 'second hit' 156 whereby the remaining allele was lost in a clone of cells has always seemed unlikely in view of the multiplicity of telangiectatic foci, and evidence that AVMs in HHT1 patients still express the same level of endoglin ( approximately one half normal) as the normal endothelial cells in the same HHT1 patient 97,157 . Large scale studies have not been presented, but it is currently believed that in most if not all cases, HHT results from endoglin or ALK-1 haploinsufficiency, that is that the remaining wild type allele is unable to contribute sufficient protein for normal function.…”

“…95 In HHT, however, assumption of a more arterial phenotype following establishment of the AV communication is not observed. The vessels within AVMs, and their draining veins are characterised by dilatation with walls of varying degrees of thickness even over relatively short segments and disorganised adventitia.Medial thinning is seen, though also prominent are areas of focal thickening with abundant elastin tissue and a varying contribution of smooth muscle cells 55,92,96,97 . Thus, in spite of perfusion at arterial pressure, the vessels immediately beyond the arteriovenous communication retain venous type wall structures.…”

“…Medial thinning is seen, though also prominent are areas of focal thickening with abundant elastin tissue and a varying contribution of smooth muscle cells 55,92,96,97 . Thus, in spite of perfusion at arterial pressure, the vessels immediately beyond the arteriovenous communication retain venous type wall structures.…”

Term neonate with intracranial hemorrhage and hereditary hemorrhagic telangiectasia: a case report and review of the literature

“…In these cases, the ICH is catastrophic and uniformly fatal, with most cases of AVM diagnosed on autopsy. 2,3 Here we report a newborn found to have HHT presenting with seizures and diagnosed with ICH from a suspected AVM who survived with aggressive medical management and surgical intervention.…”