Impaired Pulmonary Vascular Adaptation to Exercise in Emphysema without Pulmonary Hypertension – A Proof-of-Concept Study

Background: Chronic obstructive pulmonary disease with emphysema lead to respiratory disability beyond bronchial obstruction. The functional impact of pulmonary vascular lesions in emphysema remains unknown. We investigated pulmonary vascular adaptation to exercise in patients with extended emphysema.Methods: Chest magnetic resonance imaging was used to quantitatively assess right-heart function, pulmonary artery and distal pulmonary blood flow. This was performed at rest and during cycling exercise with a magnetic resonance imaging-compatible cyclo-ergometer. Seven emphysematous patients without pulmonary hypertension were compared to 7 healthy non-smokers matched in gender and age.Results: At rest, cardio-pulmonary hemodynamics and distal pulmonary vascular parameters were similar in both groups. Intrasubject adaptation to exercise in emphysematous patients was characterized by a higher increase in right-ventricular ejection fraction (ΔRVEF +8.1 vs. -2.4 %, P=0.046) though a lower right-cardiac output (4.41 vs. 5.79 L/min, P=0.04) at exercise. Accounting for right-cardiac output variation, the distal pulmonary vascular yield index trended to be decreased in patients (ΔPBF/ΔQf -0.78 vs. +18.83 %, P=0.18).Conclusions: Pulmonary vascular adaptation to exercise is impaired in emphysematous patients without identified pulmonary hypertension.Clinical trial registration NCT 04126616.

Multiscale Computational Modeling of Vascular Adaptation: A Systems Biology Approach Using Agent-Based Models

The widespread incidence of cardiovascular diseases and associated mortality and morbidity, along with the advent of powerful computational resources, have fostered an extensive research in computational modeling of vascular pathophysiology field and promoted in-silico models as a support for biomedical research. Given the multiscale nature of biological systems, the integration of phenomena at different spatial and temporal scales has emerged to be essential in capturing mechanobiological mechanisms underlying vascular adaptation processes. In this regard, agent-based models have demonstrated to successfully embed the systems biology principles and capture the emergent behavior of cellular systems under different pathophysiological conditions. Furthermore, through their modular structure, agent-based models are suitable to be integrated with continuum-based models within a multiscale framework that can link the molecular pathways to the cell and tissue levels. This can allow improving existing therapies and/or developing new therapeutic strategies. The present review examines the multiscale computational frameworks of vascular adaptation with an emphasis on the integration of agent-based approaches with continuum models to describe vascular pathophysiology in a systems biology perspective. The state-of-the-art highlights the current gaps and limitations in the field, thus shedding light on new areas to be explored that may become the future research focus. The inclusion of molecular intracellular pathways (e.g., genomics or proteomics) within the multiscale agent-based modeling frameworks will certainly provide a great contribution to the promising personalized medicine. Efforts will be also needed to address the challenges encountered for the verification, uncertainty quantification, calibration and validation of these multiscale frameworks.

Endothelial Cell PHD2-HIF1α-PFKFB3 Contributes to Right Ventricle Vascular Adaptation in Pulmonary Hypertension

Background: Humans and animals with pulmonary hypertension (PH) show right ventricular (RV) capillary growth, which positively correlates with overall RV hypertrophy. However, molecular drivers of RV vascular augmentation in PH are unknown. Prolyl hydroxylase (PHD2) is a regulator of hypoxia-inducible factors (HIFs), which transcriptionally activates several proangiogenic genes, including the glycolytic enzyme PFKFB3. We hypothesized that a signaling axis of PHD2-HIF1α-PFKFB3 contributes to adaptive coupling between the RV vasculature and tissue volume to maintain appropriate vascular density in PH. Methods and Results: We used design-based stereology to analyze endothelial cell (EC) proliferation and the absolute length of the vascular network in the RV free wall, relative to the tissue volume in mice challenged with hypoxic PH. We observed increased RV EC proliferation starting after 6 hours of hypoxia challenge. Using parabiotic mice, we found no evidence for a contribution of circulating EC precursors to the RV vascular network. Mice with transgenic deletion or pharmacologic inhibition of PHD2, HIF1α, or PFKFB3 all had evidence of impaired RV vascular adaptation following hypoxia PH challenge. Conclusions: PHD2-HIF1α-PFKFB3 contributes to structural coupling between the RV vascular length and tissue volume in hypoxic mice, consistent with homeostatic mechanisms which maintain appropriate vascular density. Activating this pathway could help augment the RV vasculature and preserve RV substrate delivery in PH, as an approach to promote RV function.

Abstract 13469: Novel Role of Extracellular SOD-derived H 2 O 2 Signaling in Exercise-induced Vascular Adaptation in Type 2 Diabetes

Background: Exercise training promotes vascular adaptation (restoration of endothelial function and angiogenesis) in type2 diabetes (T2D). Since eNOS uncoupling/O 2 - are increased in T2D, exercise may promote vascular adaptation via mechanism other than eNOS-NO axis. Extracellular superoxide dismutase (ecSOD) is a secreted copper (Cu) containing SOD that catalyzes the dismutation of O 2 - to H 2 O 2 and its full activity requires Cu transporter ATP7A. We reported that ATP7A-ecSOD pathway is reduced in T2D and that ecSOD-derived H 2 O 2 promotes VEGFR2 signaling and angiogenesis in endothelial cells. However, role of ATP7A-ecSOD axis and H 2 O 2 signaling in vascular adaptation to exercise in T2D have not been reported. Oxidation of Cysteine residues of targets proteins to generate cysteine sulfenic acid (Cys-OH) is a key initial event in H 2 O 2 -mediated signaling. Results: Here we show that ATP7A protein (49%), ecSOD activity (51%) and extracellular H 2 O 2 levels in blood vessels and skeletal muscles were significantly decreased in high fat diet-induced T2D mice compared to control C57Bl6 mice, which were rescued by volunteer wheel exercise (2 weeks) or in T2D/ATP7A overexpressing mice. In parallel, exercise training restored impaired endothelium-dependent relaxation (EDR) of resistant arteries and angiogenesis (CD31+ capillary, 2.4-fold) in skeletal muscle of T2D mice, which were inhibited by exogenous catalase or in T2D/ecSOD KO mice, but not by L-NAME, suggesting that ecSOD-derived H 2 O 2 , but not eNOS/NO, mediates exercise-induced beneficial effects. Mechanistically, exercise significantly increased Cys-OH formation of PKG1α (2.3-fold), which was shown to induce EDR in H 2 O 2 -, but not NO/cGMP-, dependent manner, in T2D vascular tissues as well as Cys-OH formation of AMPK (3.6-fold) and AMPK downstream angiogenic PGC1α and VEGF protein expression in T2D skeletal muscles. Of note, these exercise-induced Cys oxidation of PKG1α and AMPK were not observed in control or T2D/ecSOD KO mice. Conclusion: Exercise-induced ATP7A-ecSOD axis-mediated out-side in H 2 O 2 signaling plays an important role in promoting vascular adaptation in T2D via Cys oxidation of redox-sensitive kinases required for endothelial function and angiogenesis in skeletal muscles.