Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. Keywords: pulmonary circulation; vessel remodeling; angiogenesis; inflammationThe modern treatment of pulmonary arterial hypertension (PAH) has led to substantive advancements in patients' quality of life and survival, significantly improving on the grave prognosis historically associated with the disease (1, 2). With the restrictions regarding obtaining lung tissue for diagnosis, the endpoints for effectiveness of the current therapies are largely based on assessments of exercise performance and reported quality of life, time to clinical deterioration, and/or measured physiological performance (e.g., 6-min walk test). Whether prostacyclin and its analogs, endothelin receptor blockers, and phosphodiesterase type 5 inhibitors modify the spectrum of pulmonary vascular lesions in PAH has not been addressed with a large cohort of lungs with the disease.Several large series, heavily reliant on autopsy samples, highlighted pulmonary vascular alterations that characterize the pulmonary vascular remodeling in idiopathic PAH (IPAH) and PAH associated with congenital heart disease (CHD) (3-14) (see Table E1 in the online supplement). Eccentric and obliterative intima thickening are largely composed of smooth muscle cells and myofibroblasts. A similar cell composition underlies media thickening, which is regarded as the signature process in pulmonary hypertension (15). In addition, most of the cau...

Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives: To assess the spectrum of pulmonary vascular remodeling in the modern era of PAH medication. Methods: Assessment of pulmonary vascular remodeling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamic measurements. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Marked perivascular inflammation was present in a high number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH. Keywords: pulmonary circulation; vessel remodeling; angiogenesis; inflammationThe modern treatment of pulmonary arterial hypertension (PAH) has led to substantive advancements in patients' quality of life and survival, significantly improving on the grave prognosis historically associated with the disease (1, 2). With the restrictions regarding obtaining lung tissue for diagnosis, the endpoints for effectiveness of the current therapies are largely based on assessments of exercise performance and reported quality of life, time to clinical deterioration, and/or measured physiological performance (e.g., 6-min walk test). Whether prostacyclin and its analogs, endothelin receptor blockers, and phosphodiesterase type 5 inhibitors modify the spectrum of pulmonary vascular lesions in PAH has not been addressed with a large cohort of lungs with the disease.Several large series, heavily reliant on autopsy samples, highlighted pulmonary vascular alterations that characterize the pulmonary vascular remodeling in idiopathic PAH (IPAH) and PAH associated with congenital heart disease (CHD) (3-14) (see Table E1 in the online supplement). Eccentric and obliterative intima thickening are largely composed of smooth muscle cells and myofibroblasts. A similar cell composition underlies media thickening, which is regarded as the signature process in pulmonary hypertension (15). In addition, most of the cau...

Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with (13)C₃-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from (13)C₃-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.

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