Arteries can buckle axially under applied critical buckling pressure due to a mechanical instability. Buckling can cause arterial tortuosity leading to flow irregularities and stroke. Genetic mutations in elastic fiber proteins are associated with arterial tortuosity in humans and mice, and may be the result of alterations in critical buckling pressure. Hence, the objective of this study is to investigate how genetic defects in elastic fibers affect buckling pressure. We use mouse models of human disease with reduced amounts of elastin (Eln+/−) and with defects in elastic fiber assembly due to the absence of fibulin-5 (Fbln5−/−). We find that Eln+/− arteries have reduced buckling pressure compared to their wild-type controls. Fbln5−/− arteries have similar buckling pressure to wild-type at low axial stretch, but increased buckling pressure at high stretch. We fit material parameters to mechanical test data for Eln+/−, Fbln5−/− and wild-type arteries using Fung and four-fiber strain energy functions. Fitted parameters are used to predict theoretical buckling pressure based on equilibrium of an inflated, buckled, thick-walled cylinder. In general, the theoretical predictions underestimate the buckling pressure at low axial stretch and overestimate the buckling pressure at high stretch. The theoretical predictions with both models replicate the increased buckling pressure at high stretch for Fbln5−/− arteries, but the four-fiber model predictions best match the experimental trends in buckling pressure changes with axial stretch. This study provides experimental and theoretical methods for further investigating the influence of genetic mutations in elastic fibers on buckling behavior and the development of arterial tortuosity.
Background: The pleiotropic hormone relaxin has been shown to mediate physiologic responses during pregnancy by facilitating increases in vascular compliance and cardiac output. While relaxin signaling has been attributed to increases in atrial inotropy, the hormonal effects on ventricular contractility have not been explored in vivo . In this study, we investigated the dose-response effects of recombinant human relaxin (serelaxin) on ventricular mechanics. Methods and Results: Adult male CD1 mice were anesthetized and mechanically ventilated prior to Millar cardiac catheterization. A pressure-volume catheter was advanced into the left ventricle (LV), and baseline systolic and diastolic pressure/volume (PV) loops were recorded (Pre). Mice were injected with either saline, 10 μg/kg (low dose) or 1 mg/kg (high dose) of serelaxin, and PV loops were obtained after stabilization (Post) . Mice injected with 1 mg/kg demonstrated significantly higher LV contractility ( Fig A ) independent of preload ( Fig B ). These responses were not observed with low dose. In order to further examine the role of RXFP1 in modulating these responses, healthy CD1 were injected with AAV9-RXFP1 or empty vector as control and receptor overexpression was confirmed four weeks later via qPCR ( Fig C ). PV loop analysis showed an increased inotropic response [ΔP Max , Δ(dP/dt) Max ] and improved relaxation kinetics [Δ(dP/dt) Min , Δτ] in RXFP1-overexpressing mice at a lower dose of serelaxin, when compared to empty vector mice ( Fig D ). Conclusions: Our data show a novel, dose-dependent correlation between serelaxin and ventricular inotropic and lusitropic responses in mice. These responses were observed at a lower drug dose in cardiac RXFP1-overexpressing mice. We propose that further investigation of this phenomenon could advance the therapeutic, cardioprotective effects associated with relaxin therapy in different etiologies of heart failure that may exhibit changes in RXFP1 expression.
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