Beschreibung:
<jats:p>Pulmonary arterial hypertension (PAH) is a devastating disease, with increased pulmonary arterial pressure leading to right heart failure. The mechanisms underlying PAH are unclear, but increased pulmonary arterial smooth muscle (PASMC) and microvascular endothelial cell (MVEC) migration and proliferation leads to vaso‐occlusive lesions and vascular remodeling observed in PAH. Aquaporins regulate water transport and are expressed in many cells. We previously identified that hypoxia upregulates the expression of aquaporin 1 (AQP1) in PASMC and elevated AQP1 was required for hypoxia‐induced migration and proliferation. In this study, we wanted to elucidate whether the same is true in MVECs, and used the SU5416 plus hypoxia (SuHx) rat model, a robust model of PAH, which mimics many of the features of human PAH, to determine whether AQP1 levels were altered in MVECs and contributed to a hyperproliferative/hypermigratory phenotype.</jats:p><jats:p>Rats were injected with the vascular endothelial growth factor receptor inhibitor, SU5416, combined with hypoxia (3 wk at 10% O2) followed by 2 wk return to normoxia. Using MVECs isolated from the normoxia (N‐MVEC) or SuHx (SuHx‐MVEC) rats, we found that AQP1 protein levels were increased in SuHx‐MVECs and associated with upregulation of AQP1 mRNA levels, even in the absence of sustained hypoxia exposure. Silencing of AQP1 reduced migration and proliferation observed in SuHx‐MVEC, whereas augmenting AQP1 levels in N‐MVECs using forced expression with an adenoviral construct containing wild‐type AQP1 (AdAQP1) was sufficient to increase cell migration (transwell assay) and proliferation (BrdU incorporation) compared to control cells infected with green fluorescent protein (AdGFP). Since we formerly reported the C‐terminal tail of AQP1 contains putative calcium and protein biding sites and is required for enhanced PASMC migration and proliferation, we tested the role of the AQP1 C‐terminal tail in N‐MVEC. Cells were treated with AdGFP, AdAQP1 or adenovirus containing AQP1 lacking the entire cytoplasmic C‐terminal tail (AdAQP1CT). In contrast to the increase in migration and proliferation induced by AdAQP1, infection with AdAQP1CT did not alter N‐MVEC migration and proliferation.</jats:p><jats:p>Our results suggest a key role for enhanced AQP1 expression in mediating abnormal migration and proliferation in microvascular endothelial cells from a rodent model that reflects many of the features of human PAH. Interestingly, the AQP1 C‐terminal tail is required for regulating MVEC function, similar to our previous findings in PASMC.</jats:p>