Extracellular matrix remodeling has been proposed as one mechanism by which proximal pulmonary arteries stiffen during pulmonary arterial hypertension (PAH). Although some attention has been paid to the role of collagen and metallomatrix proteins in affecting vascular stiffness, much less work has been performed on changes in elastin structure-function relationships in PAH. Such work is warranted, given the importance of elastin as the structural protein primarily responsible for the passive elastic behavior of these conduit arteries. Here, we study structure-function relationships of fresh arterial tissue and purified arterial elastin from the main, left, and right pulmonary artery branches of normotensive and hypoxia-induced pulmonary hypertensive neonatal calves. PAH resulted in an average 81 and 72% increase in stiffness of fresh and digested tissue, respectively. Increase in stiffness appears most attributable to elevated elastic modulus, which increased 46 and 65%, respectively, for fresh and digested tissue. Comparison between fresh and digested tissues shows that, at 35% strain, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue is due to the change in elastin stiffness. Analysis of the stress-strain behavior revealed that PAH causes an increase in the strains associated with the physiological pressure range but had no effect on the strain of transition from elastin-dominant to collagen-dominant behavior. These results indicate that mechanobiological adaptations of the continuum and geometric properties of elastin, in response to PAH, significantly elevate the circumferential stiffness of proximal pulmonary arterial tissue.
Although production of reactive oxygen species (ROS) such as superoxide (O(2)(.-)) has been implicated in chronic hypoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling, the transcription factors and gene targets through which ROS exert their effects have not been completely identified. We used mice overexpressing the extracellular antioxidant enzyme extracellular superoxide dismutase (EC-SOD TG) to test the hypothesis that O(2)(.-) generated in the extracellular compartment under hypoxic conditions contributes to PH through the induction of the transcription factor, early growth response-1 (Egr-1), and its downstream gene target, tissue factor (TF). We found that chronic hypoxia decreased lung EC-SOD activity and protein expression in wild-type mice, but that EC-SOD activity remained five to seven times higher in EC-SOD TG mice under hypoxic conditions. EC-SOD overexpression attenuated chronic hypoxic PH, and vascular remodeling, measured by right ventricular systolic pressures, proliferation of cells in the vessel wall, muscularization of small pulmonary vessels, and collagen deposition. EC-SOD overexpression also prevented the early hypoxia-dependent upregulation of the redox-sensitive transcription factor Egr-1 and the procoagulant protein TF. These data provide the first evidence that EC-SOD activity is disrupted in chronic hypoxia, and increased EC-SOD activity can attenuate chronic hypoxic PH by limiting the hypoxic upregulation of redox-sensitive genes.
Significant race/ethnicity-based disparities in AHT evaluation and reporting were observed at only 2 of 18 sites and occurred almost exclusively in lower risk patients. In the absence of local confounders, these disparities likely represent the impact of local physicians' implicit bias.
Developing clinical work suggests that vascular stiffening plays a role in the progression of pulmonary hypertension (PH), while recent studies in animal models of hypoxic PH have found significant proximal vascular stiffening in the diseased population. Here, we develop and validate a minimally invasive, clinically realizable method to estimate the local elastic modulus of the proximal pulmonary arteries from pressure-diameter (PD) data. PD measurements were made in the main pulmonary arteries of 16 calves; lumen diameter was assessed using color M-mode tissue Doppler imaging ultrasound, while pressure was measured via catheter. Two methods corresponding to thin-walled pressure vessel theory ("thin") and Lame's equation for a thick-walled cylinder ("thick") were used to approximate the artery elastic modulus from PD measurements. The harvested arteries were tested independently to determine their "true" ex vivo elastic modulus and stiffness. Both approximations displayed excellent correlation with ex vivo elastic modulus of the calf main pulmonary artery (thin r(2) = 0.811; thick r(2) = 0.844; both P < 0.01). Bland-Altman analysis indicated that the thick-walled approximation has better overall agreement with ex vivo modulus. The approximations displayed quantitatively distinct regression slopes that were statistically different (P = 0.02). The elastic modulus of the main pulmonary artery can be reasonably estimated from combined color M-mode tissue Doppler imaging ultrasound and catheter pressure measurements in calves. Such measurements may be a valuable tool in the diagnosis and treatment of human PH.
With 1 hour of practice time, requiring 15 minutes of direct teaching, novice resident bronchoscopists are able to more accurately identify and visualize the five lung lobes and lingula via FB and are able to do so in less time than control residents. This anatomically accurate model could be used to train basic FB skills at a low cost compared with other models.
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