Proangiogenic and wound healing molecular and histological fingerprint of chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a multifactorial disease initiated by pulmonary thromboembolism, leading to death if unrecognized and untreated. We intend to characterize and compare the distal remodeling in CTEPH with idiopathic PH (IPAH), in terms of histological and molecular phenotyping, employing transplanted CTEPH, IPAH and donor human lungs. Transplanted CTEPH, IPAH and donor lung tissues (n=12) were proceeded to laser capture microdissection (LCM) of vessels, followed by RNA isolation and microarray screening. Assessment of vascular remodeling, inflammatory cell composition and collagen quantification was followed after histochemical stainings. Additionally, total microvessel density was calculated from vWF, CD31 and CD34 stainings. Morphometric analysis confirmed similar extent of medial hypertrophy, but differences in collagen deposition and vascularization between CTEPH and IPAH lungs, as compared to donors. Bioinformatics analysis of the microarray data revealed differentially (607) and similarly (366) regulated genes and gene networks. Our in vitro data suggest that two of the differentially regulated genes, CHI3L1 and ENPP2 play an important role in neovascularization and migration of smooth muscle cells and fibroblasts. These studies highlight the similarities and difference in terms of histological and molecular networks between different groups of PH. Further in vitro and in vivo studies will provide more knowledge into the molecular mechanism playing a role in the disease and can possibly contribute to identify novel therapeutic targets.