García-Sanmartín Josune, Narro-Íñiguez Judit, Rodríguez-Barbero Alicia, Martínez Alfredo
Angiogenesis Unit, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006 Logrono, Spain.
Vascular Endothelium Pathophysiology (ENDOVAS) Unit, Department of Physiology and Pharmacology, University of Salamanca, 37007 Salamanca, Spain.
Biology (Basel). 2022 Feb 24;11(3):358. doi: 10.3390/biology11030358.
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 () and activin receptor-like kinase 1 () 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 and mutants that have not yet been studied and that may offer, in the future, a new focus for research on HHT.
遗传性出血性毛细血管扩张症（HHT）是一种罕见疾病，其特征为血管畸形和大量出血。该疾病由骨形态发生蛋白-9（BMP-9）受体成分：内皮糖蛋白（ENG）和激活素受体样激酶1（ALK1）基因的突变引起。最近，我们报道HHT患者血清肾上腺髓质素（AM）水平高于健康志愿者；因此，我们通过酶免疫测定、定量逆转录聚合酶链反应（qRT-PCR）、免疫组织化学和蛋白质免疫印迹法研究了缺乏任一受体成分的小鼠中AM的表达，以调查这些缺陷是否可能是患者AM升高的原因。我们发现AM表达并未以一致模式受这些突变影响。相反，在一些器官（血液、肺、胃、胰腺、心脏、肾脏、卵巢、大脑皮质、海马体、足部皮肤和微血管）中，没有显著变化，而在其他器官中，我们发现要么表达降低（脂肪、皮肤和肾上腺），要么AM产生增加（小脑和结肠）。这些结果与我们最初的假设相矛盾，即HHT患者中发现的AM表达增加可能直接归因于突变，但引发了关于ENG和ALK1突变体潜在表型表现的有趣问题，这些问题尚未得到研究，未来可能为HHT研究提供新的重点。
