Impact of GLP1R and its agonists in pulmonary circulation

<bold>Background:</bold> The approved use of GLP1R agonists for the treatment of diabetes has shown positive effects on the cardiovascular system. GLP1R is highly expressed in the pulmonary circulation, but the role of GLP1R in the pulmonary circulation is still largely unknown. Given the severity of pulmonary arterial hypertension (PAH), there is an urgent need to explore new treatment options. Therefore, we sought to explore the role of GLP1R in the pulmonary vasculature. <bold>Methods:</bold> GLP1R was silenced to confirm the specificity of the monoclonal antibody used to stain GLP1R in embedded human lung slices. qPCR was performed on laser capture microdissected (LCM) pulmonary arteries (PA) from PAH and donor lungs. Both human pulmonary smooth muscle (hPASMC) and endothelial cells (hPAECs) were used to study the proliferative effects of the GLP1R agonist (liraglutide). Isolated human and rat arteries were examined for the acute effect of GLP1R agonist on vascular tone. <bold>Results:</bold> GLP-1R was observed in PAs, particularly in hPAECs and hPASMCs. In LCM PAs, GLP1R is increased at the mRNA level in PAH compared to donors. Liraglutide increased cAMP production in hPASMCs. Notably, liraglutide showed an inhibitory effect on the proliferation of both hPASMCs and hPAECs. In a wire myograph, liraglutide at high concentrations had vasodilatory effects in both human and rat PAs. Furthermore, in an IPL model, the vasodilator effect of liraglutide was maintained even in the absence of GLP-1R, suggesting possible alternative pathways for its action. <bold>Conclusion:</bold> Liraglutide shows an antiproliferative effect in hPASMCs and hPAECs. In addition, it induces vasodilation independent of its receptor, suggesting a potential therapeutic benefit in the treatment of PAH.