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.

Synchronization of time-varying coupled complex networks via adaptive pinning control

Pinning synchronization of complex networks with two different kinds of time-varying coupling are studied in this paper. Inner coupling of the state variables and outer coupling in the complex network are taken into consideration. Based on the Lyapunov function theory, some general criteria and a simplified corollary for ensuring network synchronization are proposed. Linear pinning controllers, adaptive pinning controllers and adaptive coupling strength are designed for achieving complex network time-varying synchronization. Furthermore, the analytic relationship between control parameters is studied. Numerical simulations further illustrate the effectiveness of conclusions.

Interplay of random inputs and adaptive couplings in the Winfree model

<p style='text-indent:20px;'>We study a structural robustness of the complete oscillator death state in the Winfree model with random inputs and adaptive couplings. For this, we present a sufficient framework formulated in terms of initial data, natural frequencies and adaptive coupling strengths. In our proposed framework, we derive propagation of infinitesimal variations in random space and asymptotic disappearance of random effects which exhibits the robustness of the complete oscillator death state for the random Winfree model.</p>