Endoglin and activin receptor-like-kinase 1 are co-expressed in the distal vessels of the lung: implications for two familial vascular dysplasias, HHT and PAH

Arteriovenous malformations (AVMs) are direct connections between arteries and veins associated with loss of the intervening capillary bed. In the lungs, pulmonary AVMs can result in right to left shunts and severe cyanosis and dyspnoea. However, the cellular and molecular mechanisms underlying AVM formation are poorly understood. One important clue comes from the fact that pulmonary AVMs frequently occur in the familial disease hereditary haemorrhagic telangiectasia (HHT), which is associated with mutations in one of two receptors involved in transforming growth factor-beta family signalling, either endoglin (ENG) or activin receptor-like kinase 1 ( ACVRL1, also known as ALK1). To elucidate the potential link between ENG or ACVRL1 deficiency and AVM formation in HHT, we performed a comprehensive study of Acvrl1 and Eng expression in wild-type and Eng-deficient (Eng+/-) mouse lungs using a combination of immunohistochemistry and RT-PCR from laser-microdissected arteries, veins and capillaries. We found that Eng and Acvrl1 have distinct expression profiles in the pulmonary vasculature and are only co-expressed in the distal (pre-capillary) arteries, distal veins and capillaries, consistent with the tendency for pulmonary AVMs to form in the distal pulmonary vessels in HHT. Downstream pSmad1/5/8 activity was found in the distal arteries and was specifically reduced in Eng+/- mice, consistent with previous in vitro data showing that Eng promotes Acvrl1-mediated Smad 1/5/8 phosphorylation. Eng was more widely expressed than Acvrl1 in the lungs, as Eng alone was found in pulmonary veins, potentially explaining the increased frequency of AVMs in HHT1 patients. Furthermore, the association of ACVRL1 mutations with a second vascular disease, familial pulmonary artery hypertension, underlines the importance of ACVRL1 expression in the distal arteries that are affected in this disorder.