Conduit pulmonary artery (PA) stiffening is characteristic of pulmonary arterial hypertension (PAH) and is an excellent predictor of mortality due to right ventricular (RV) overload. To better understand the impact of conduit PA stiffening on RV afterload, it is critical to examine the arterial viscoelastic properties, which require measurements of elasticity (energy storage behavior) and viscosity (energy dissipation behavior). Here we hypothesize that PAH leads to frequency-dependent changes in arterial stiffness (related to elasticity) and damping ratio (related to viscosity) in large PAs. To test our hypothesis, PAH was induced by the combination of chronic hypoxia and an antiangiogenic compound (SU5416) treatment in mice. Static and sinusoidal pressure-inflation tests were performed on isolated conduit PAs at various frequencies (0.01–20 Hz) to obtain the mechanical properties in the absence of smooth muscle contraction. Static mechanical tests showed significant stiffening of large PAs with PAH, as expected. In dynamic mechanical tests, structural stiffness (κ) increased and damping ratio (D) decreased at a physiologically relevant frequency (10 Hz) in hypertensive PAs. The dynamic elastic modulus (E), a material stiffness, did not increase significantly with PAH. All dynamic mechanical properties were strong functions of frequency. In particular, κ, E and D increased with increasing frequency in control PAs. While this behavior remained for D in hypertensive PAs, it reversed for κ and E. Since these novel dynamic mechanical property changes were found in the absence of changes in smooth muscle cell content or contraction, changes in collagen and proteoglycans and their interactions are likely critical to arterial viscoelasticity in a way that has not been previously described. The impact of these changes in PA viscoelasticity on RV afterload in PAH awaits further investigation.

The aims of this chapter are to review the current state of knowledge regarding the viscoelastic behavior of cardiovascular tissues. We begin with a brief, general discussion of measurement and modeling of cardiovascular tissue viscoelasticity. We then review known viscoelastic behavior of arteries, veins, capillaries, blood components, the heart, and lymphatics. For each tissue type, we highlight tissue-specific measurement methods, the cellular and extracellular components responsible for tissue viscoelasticity, and the clinical implications of energy loss due to viscoelasticity. We conclude with a summary and suggestions for future research.

Pulmonary arterial hypertension (PAH) is a severe form of pulmonary hypertension in which right ventricular (RV) afterload is increased and death typically occurs due to decompensated RV hypertrophy and failure. Collagen accumulation has been implicated in pulmonary artery remodeling, but how it affects RV performance remains unclear. Here, we sought to identify the role of collagen turnover, defined as the balance between collagen synthesis and degradation, in RV structure and function in PAH. To do so, we exposed mutant (Col1a1R/R) mice, in which collagen type I degradation is impaired such that collagen turnover is reduced, and wild‐type (Col1a1+/+) littermates to 14 days of chronic hypoxia combined with SUGEN treatment (HySu) to recapitulate characteristics of clinical PAH. RV structure and function were measured by echocardiography, RV catheterization, and histology. Despite comparable increases in RV systolic pressure (Col1a1+/+: 46 ± 2 mmHg; Col1a1R/R: 47 ± 3 mmHg), the impaired collagen degradation in Col1a1R/R mice resulted in no RV collagen accumulation, limited RV hypertrophy, and maintained right ventricular‐pulmonary vascular coupling with HySu exposure. The preservation of cardiac function in the mutant mice indicates a beneficial role of limited collagen turnover via impaired degradation in RV remodeling in response to chronic pressure overload. Our results suggest novel treatments that reduce collagen turnover may offer a new therapeutic strategy for PAH patients.

Pulmonary arterial hypertension (PAH), a rapidly fatal vascular disease, strikes women more often than men. Paradoxically, female PAH patients have better prognosis and survival rates than males. The female sex hormone 17β-estradiol has been linked to the better outcome of PAH in females; however, the mechanisms by which 17β-estradiol alters PAH progression and outcomes remain unclear. Since proximal PA stiffness, one hallmark of PAH, is a powerful predictor of mortality and morbidity, we hypothesized that 17β-estradiol attenuates PAH-induced changes in mechanical properties in conduit proximal PAs, which imparts hemodynamic and energetic benefits to RV function. To test this hypothesis, female mice were ovariectomized and treated with 17β-estradiol or placebo. PAH was induced in mice using SU5416 and chronic hypoxia (SuHx). Extra-lobar left PAs were isolated and mechanically tested ex vivo to study both static and frequency-dependent mechanical behaviors in the presence or absence of SMC activation. Our static mechanical test showed significant stiffening of large PAs with PAH (P < 0.05). 17β-estradiol restored PA compliance to control levels. The dynamic mechanical test demonstrated that 17β-estradiol protected the arterial wall from the PAH-induced frequency-dependent decline in dynamic stiffness and loss of viscosity with PAH (P<0.05). As demonstrated by the in vivo measurement of PA hemodynamics via RV catheterization, modulation by 17β-estradiol of mechanical proximal PAs reduced pulsatile loading, which contributed to improved ventricular-vascular coupling. This study provides a mechanical mechanism for delayed disease progression and better outcome in female PAH patients and underscores the therapeutic potential of 17β-estradiol in PAH.