Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, with an epidemiology similar to that of pulmonary arterial hypertension (PAH). CTEPH is a subgroup of pulmonary hypertension (PH) with a cumulative incidence between 0.1% and 9.1% in patients with reported pulmonary embolism. The state-of-the-art therapeutic strategy is pulmonary endarterectomy (PEA). Yet, approximately 60% of the patients are eligible for surgery and significant number of patients develop persistent/recurrent PH after PEA. Furthermore, around 25% of patients with subsegmental obstruction are candidates for balloon angioplasty (BPA), and/or medical therapy, developed and used in the past few years. Hence, better understanding of the pathophysiology and molecular mechanisms driving the CTEPH is mandatory in order to identify effective treatments especially for patients with absence of proximal obliteration. The existence of microvascular disease in CTEPH, indistinguishable from idiopathic PAH (IPAH) was at first acknowledged by Moser and Bloor in a lung tissues obtained from biopsy or at autopsy of CTEPH patients. On one hand, the vascular lesions exhibited eccentric intimal fibrosis, intimal fibromuscular proliferation, medial hypertrophy and presence of plexiform lesions. On the other hand, it was postulated that the vascular remodelling distal to the thromboembolic obstruction may be similarly distributed in the lung areas of complete and non-complete occlusion CTEPH. Based on prior research, the following research questions are of interest to better understand the CTEPH: (1) Are the molecular and histological imprints of CTEPH comparable or distinct to the extensively studied PAH? (2) Are there significant differences from histological or molecular aspect between the vascular lesions in proximal (central) and distal (peripheral) CTEPH? (3) Is the small vessel arteriopathy homogeneously distributed in different lobes, irrespective of the site of the disease? (4) Are the lung biopsies from patients who develop PH due to sarcoma resembling the classical histopathological changes observed in CTEPH? (5) What is the functional role of the unbiasedly selected targets in terms of development or maintenance of CTEPH?In order to answer these research questions, this thesis aim to histologically and molecularly characterize the end-stage CTEPH enfolding several facets and further, the ongoing CTEPH in terms of central and occluded (completely and non-completely) vascular lesions. First, multi-centre human samples have been collected and investigated to identify whether vascular remodelling in the end-stage CTEPH is as similar as in the other groups of PH, esp. in the well-studied idiopathic PAH group. Different morphometric approaches were applied to assess the vascular remodelling. Next, the analysis of global transcriptional landscape in CTEPH and IPAH was performed from laser capture microdissected vessels, to identify the common or the unique mechanisms driving small vessel arteriopathy in CTEPH as compared to IPAH. These findings suggest that the distal vascular remodelling in CTEPH, resemble vascular remodelling in IPAH. Furthermore, CTEPH manifests significantly divergent global transcriptional landscape in comparison to IPAH.Second, the results show that central manifest similar histological changes as peripheral CTEPH, while the global transcriptional landscape of central CTEPH manifests similar and unique signaling pathways in contrast to the peripheral CTEPH. Third, the results show that small vessel arteriopathy is homogeneously distributed in different lobes, irrespective of the site of the disease. Forth, similarly patients who develop PH due to sarcoma and underwent PEA present comprehensive vascular remodelling, similar to end-stage CTEPH patients. Fifth, it is revealed that CHI3L1 and ENPP2, differently regulated genes between CTEPH and IPAH, and similarly regulated in proximal and distal CTEPH, are involved in pulmonary vascular remodelling in vitro and ex vivo via regulation of pro-proliferative, pro-migratory and pro-contractile mechanisms, suggesting a potential contribution to the pathogenesis of CTEPH.Taken together, further studies are needed to understand how exact factors, such as high share stress, hypoxia or inflammatory molecules trigger the interlaying pathological and molecular mechanisms in CTEPH.
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