write a summary :Currently used animal and cellular models for pulmonary arterial hypertension (PAH) only partially recapitulate its pathophysiology in humans and are thus inadequate in reproducing the hallmarks of the disease, inconsistent in portraying the sex-disparity, and unyielding to combinatorial study designs. Here we sought to deploy the ingenuity of microengineering in developing and validating a tissue chip model for human PAH. We designed and fabricated a microfluidic device to emulate the luminal, intimal, medial, adventitial, and perivascular layers of a pulmonary artery. By growing three types of pulmonary arterial cells (PACs)-endothelial, smooth muscle, and adventitial cells, we recreated the PAH pathophysiology on the device. Diseased (PAH) PACs, when grown on the chips, moved of out their designated layers and created phenomena similar to the major pathologies of human PAH: intimal thickening, muscularization, and arterial remodeling and show an endothelial to mesenchymal transition. Flow-induced stress caused control cells, grown on the chips, to undergo morphological changes and elicit arterial remodeling. Our data also suggest that the newly developed chips can be used to elucidate the sex disparity in PAH and to study the therapeutic efficacy of existing and investigational anti-PAH drugs. We believe this miniaturized device can be deployed for testing various prevailing and new hypotheses regarding the pathobiology and drug therapy in human PAH. Pulmonary arterial hypertension (PAH) is a rare disease in which pulmonary arteries/arterioles become stiffer and occluded. Thus, the heart has to work harder to pump blood through the occluded arteries into the lungs. In so doing, the heart becomes enlarged and patients die of right heart failure. The chief clinical manifestation of the disease is elevated mean pulmonary arterial pressure that results from an array of active structural alterations in the pulmonary artery, called arterial remodeling and muscularization. This pathology develops because of aberrant proliferation, migration and misplaced growth of pulmonary arterial cells (PACs), development of apoptosis-resistant endothelial cells (ECs), enhanced deposition of extracellular matrices (ECMs), thickening of smooth muscle layers, and acquisition of smooth muscle cell (SMC)-like phenotypes by ECs.1,2 One of the puzzling aspects of PAH is that it affects more women than men but women with PAH tend to live longer than men. This disparity in the prevalence versus survival of PAH patients is believed to result from intrinsic differences between the two sexes and the conflicting roles of sex hormones, especially estrogen, which appear to have both beneficial and detrimental effects in the genesis and progression of PAH in females.3 In fact, the genesis of the disease centers around the interactions of the three major cells of the pulmonary arteries/arterioles-ECs, SMCs, and adventitial cells (ADCs) that are chiefly fibroblasts. For studying the pathogenesis, potential therapies, and sex disparity in PAH, investigators have traditionally relied on various animal models that most commonly include chronic hypoxia, Sugen-5416-plus-hypoxia (SuHx), and monocrotaline (MCT)-induced models as well as various genetically-modified mouse models.4 By reproducing the chief feature of the disease, elevated pulmonary arterial pressure, these models have aided in our understanding of the pathobiology and evaluating therapeutic interventions. However, existing animal models only partially recapitulate the important pathological changes of human PAH such as the arteriopathy with neointimal and plexiform lesions and progressive deterioration of the disease.5 Because the development of animal models entails the use of various animal species and distinct disease-producing agents or environments, animal models of PAH show a great deal of variability in the disease severity, progression, and response to therapeutic interventions.6 Cellular models that have been used to elucidate PAH pathology and assess drug therapy include mono- and co-cultures of ECs, SMCs, or ADCs collected from the pulmonary arteries of rodent and bovine models of PAH and from human PAH patients. These two-dimensional (2D) models, conse

Question

Accepted Answer

The passage is about pathophysiology and course of development of pulmonary arterial hypertension (…