Friday, April 26, 2024
4/26/2024
PROJECT SUMMARY Pulmonary artery and capillary endothelial cells are structurally and functionally heterogeneous in multiple ways including their inflammatory response. In pulmonary arterial hypertension (PAH), CD68-positive monocytes accumulate around arterioles as opposed to migrating into the alveolar space as they do in acute lung injury. Further, inflammatory infiltrates are a feature of late-stage disease, are localized to small arterioles, and are not as observable in the early stages of PAH. The contributions of the inflammatory cell infiltrates include release of growth factors and further inflammatory stimuli. The precise mechanisms that influence the temporal recruitment of inflammatory cells to the perivascular space in select size vessels and the influence of the phenotypically distinct endothelium remain unknown. Microparticle signaling within phenotypically distinct endothelium has not been considered and could have significant implications toward adhesion molecule expression. We found that microparticles from late-stage PAH rats were endocytosed and localized to the perinuclear space in pulmonary artery endothelial cells (PAECs), induced adhesion molecule expression, and promoted leukocyte adhesion. However, none of these events occurred in pulmonary microvascular endothelium (PMVECs) with the same treatment. Further, microparticles isolated from the circulation of early- stage PAH rats had none of these effects on either cell type. To determine the mechanism of microparticle signaling in the PAECs we examined Rab proteins responsible for vesicle trafficking and intracellular localization. RNAseq analysis and RT-PCR of PAECs and PMVECs revealed Rab36 is expressed only in the PAECs. Rab36 is a newly identified RabGTPase responsible for retrograde transport of vesicles to the Golgi and nucleus. Based on these data this proposal tests the overall HYPOTHESIS that late-stage microparticles, circulating in PAH, increase adhesion molecule expression selectively in the pulmonary arteries dependent on Rab36. SPECIFIC AIMS test the hypotheses that circulating microparticles obtained from late-stage, but not early-stage PAH: 1. Stimulate expression and activity of adhesion molecules selectively in the pulmonary artery. 2. Are dependent on Rab36 for uptake and subcellular localization in the pulmonary artery.
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