Simple Summary
Hereditary hemorrhagic telangiectasia (HHT) is called a rare disease because it affects relatively few people. It is characterized by malformations in some blood vessels and usually results in profuse nose bleedings. In a recent article, we found that these patients have higher levels of adrenomedullin (AM), a molecule with cardiovascular activities, than healthy people. Thus we wanted to know whether the mutations that cause the HHT disease are directly responsible for these higher levels of AM. To investigate this issue, we used mutant mice, which express lower levels of the genes involved in the disease (called Eng and Acvrl1), and measured how much AM was found in different tissues. Although we expected a higher amount of AM in all organs, that was not the case. Some organs showed no variation, some had lower levels of AM than normal mice (fat, skin, and adrenals), and others had a higher expression (cerebellum and colon). Interestingly, our results suggest that these genes and the related molecule BMP-9 may have novel functions, which have not been yet investigated, which may shed more light on the physiopathology of HHT.
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a rare disease characterized by vascular malformations and profuse bleeding. The disease is caused by mutations in the components of the BMP-9 receptor: endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1) genes. Recently, we reported that HHT patients expressed higher serum levels of adrenomedullin (AM) than healthy volunteers; thus, we studied the expression of AM (by enzyme immunoassay, qRT-PCR, immunohistochemistry, and Western blotting) in mice deficient in either one of the receptor components to investigate whether these defects may be the cause of that elevated AM in patients. We found that AM expression is not affected by these mutations in a consistent pattern. On the contrary, in some organs (blood, lungs, stomach, pancreas, heart, kidneys, ovaries, brain cortex, hippocampus, foot skin, and microvessels), there were no significant changes, whereas in others we found either a reduced expression (fat, skin, and adrenals) or an enhanced production of AM (cerebellum and colon). These results contradict our initial hypothesis that the increased AM expression found in HHT patients may be due directly to the mutations, but open intriguing questions about the potential phenotypic manifestations of Eng and Acvrl1 mutants that have not yet been studied and that may offer, in the future, a new focus for research on HHT.