Michelle P. Bendeck

Pulmonary artery compliance and stiffness are increasingly recognized as contributors to outcomes in pulmonary arterial hypertension (PAH). We report significant associations between main pulmonary artery (MPA) pulsatility and gold standard measures of MPA stiffness, components of right ventricular (RV) afterload, function, and RV-PA coupling in experimental and in patients with iPAH. Our findings suggest that MPA pulsatility is a simple, accessible surrogate to MPA stiffness that may facilitate the assessment of prognostically important factors in PAH.

Background: Aortic microstructure-function relationships and the pathophysiology of how medial degeneration leads to aortic dissection remain poorly defined. We aimed to determine how degeneration of individual components of the extracellular matrix (ECM), namely elastin, collagen, and proteoglycans, influence biomechanical properties of aortic tissue through an improved, disease-motivated enzymatic digestion framework. Methods: Porcine aortic tissue was sectioned into 200 µm thick samples in the media, and progressively digested with elastase or collagenase for selective degradation of these ECM components. Full thickness human aortic tissues were treated with chondroitinase, hyaluronidase, and heparinase to completely remove proteoglycans. Biomechanical characterization was performed using planar biaxial tensile testing, from which low- and high-strain modulus, transition-zone behaviour, strain-energy density, and energy loss were derived. Degree of elastin fiber degradation was analyzed using two photon excitation fluorescence imaging. Analysis of collagen degradation was performed using picrosirius red staining under brightfield and polarized light. Alcian blue staining was used to evaluate proteoglycan content. Results: Induced fragmentation and disorganization of elastin fibers reduced low-strain load bearing capacity, evidenced by reduced low-strain modulus, strain-energy density, and transition zone stress, along with reduced energy loss. Targeted collagen disorganization similarly reduced strain-energy density and decreased strain at the onset of transition, consistent with premature collagen recruitment, and was accompanied by reductions in high strain modulus and energy loss with increasing collagen degradation. Proteoglycan removal decreased energy loss and was found to modulate low- and high-strain behaviour, including reduced strain-energy density and strain at onset of transition, and increased high strain modulus. Conclusions: Through targeted modelling of ECM degenerative features on aortic tissue mechanics, we have identified distinct disease-associated biomechanical roles for major matrix constituents, with overlapping effects. These findings delineate mechanical consequences of component-specific matrix degeneration while underscoring the complex, multifactorial nature of structure-function relationships in aortic disease.

BACKGROUND: Coupling between right ventricular (RV) function and the pulmonary vasculature determines outcomes in pulmonary arterial (PA) hypertension. The mechanics of the main PA (mPA) is an important but understudied determinant of RV-PA coupling. To investigate the histology and mechanics of PA in relationship to RV remodeling, mechanics, hemodynamics, and coupling in experimental PA hypertension. METHODS: In a sugen-hypoxia rat model of PA hypertension, RV hemodynamics were assessed by conductance catheters. Active tension-strain curves were generated using echocardiography. mPA and RV free wall were harvested to determine their macrostructure and microstructure, composition, and mechanical properties. Comprehensive multivariate analyses elucidated relationships between PA and RV mechanics, structure, and coupling. RESULTS: Pulmonary hypertensive mPAs developed fibrosis relative to healthy controls, as did RVs, which also hypertrophied, with reorientation of muscle fibers toward a trilayer architecture reminiscent of normal left ventricular architecture. Increased glycosaminoglycan deposition and increased collagen-to-elastin ratio in PA, and increased collagen, as well as hypertrophy and reorganization of myofibers in RV, led to increased stiffness. This increase in stiffness was more pronounced in the longitudinal direction in the high- and low-strain regime for PA and RV, respectively, causing increased mechanical anisotropy. mPA stiffening correlated significantly with RV tissue mechanical remodeling and reduced systolic performance, cardiac output, and RV-PA coupling. CONCLUSIONS: Compositional, structural, and mechanical changes in mPA correlate with adverse RV remodeling, mechanics, function, and coupling in PA hypertension. Therefore, increasing mechanical compliance of the large PAs may be an important and novel therapeutic strategy for mitigating RV failure.

Rationale Coupling between right ventricular function and the pulmonary vasculature determines outcomes in pulmonary arterial hypertension. The mechanics of the main pulmonary artery is an important but understudied determinant of right ventricular-pulmonary artery coupling. Objectives To investigate the histology and mechanics of the pulmonary artery in relationship to right ventricular remodeling, mechanics, hemodynamics and coupling in experimental pulmonary arterial hypertension. Methods In a sugen+hypoxia rat model of pulmonary arterial hypertension, right ventricular hemodynamics were assessed by conductance catheters. Active tension-strain curves were generated using echocardiography. Main pulmonary artery and right ventricle free-wall were harvested to determine their macro- and micro-structure, composition, and mechanical properties. Comprehensive multivariate analyses elucidated relationships between pulmonary artery and right ventricle mechanics, structure and coupling. Measurements and Main Results Pulmonary hypertensive main pulmonary arteries developed fibrosis relative to healthy controls, as did right ventricles, which also hypertrophied, with re-orientation of muscle fibres toward a tri-layer architecture reminiscent of normal left ventricular architecture. Increased glycosaminoglycan deposition and increased collagen-to-elastin ratio in the pulmonary artery; and increased collagen, as well as hypertrophy and reorganization of myofibers in the right ventricle, led to increased stiffness. This increase in stiffness was more pronounced in the longitudinal direction in the high- and low-strain regime for the pulmonary artery and right ventricle, respectively, causing increased mechanical anisotropy. Main pulmonary artery stiffening correlated significantly with right ventricular tissue mechanical remodelling and reduced systolic performance, cardiac output and right ventricle-pulmonary artery coupling. Conclusions Compositional, structural, and mechanical changes in the main pulmonary artery correlate with adverse right ventricular remodeling, mechanics, function and coupling in pulmonary arterial hypertension. Therefore, increasing mechanical compliance of the large pulmonary arteries may be an important and novel therapeutic strategy for mitigating right ventricular failure.

BACKGROUND: Treatment of occluded vessels can involve angioplasty, stenting, and bypass grafting, which can be limited by restenosis and thrombosis. Drug-eluting stents attenuate restenosis, but the current drugs used are cytotoxic, causing smooth muscle cell (SMC) and endothelial cell (EC) death that may lead to late thrombosis. N-cadherin is a junctional protein expressed by SMCs, which promotes directional SMC migration contributing to restenosis. We propose that engaging N-cadherin with mimetic peptides can act as a cell type–selective therapeutic strategy to inhibit polarization and directional migration of SMCs without negatively impacting ECs. METHODS: We designed a novel N-cadherin–targeting chimeric peptide with a histidine-alanine-valine cadherin-binding motif, combined with a fibronectin-binding motif from Staphylococcus aureus . This peptide was tested in SMC and EC culture assays of migration, viability, and apoptosis. Rat carotid arteries were balloon injured and treated with the N-cadherin peptide. RESULTS: Treating scratch-wounded SMCs with the N-cadherin–targeting peptide inhibited migration and reduced polarization of wound-edge cells. The peptide colocalized with fibronectin. Importantly, EC junction, permeability, or migration was not impacted by peptide treatment in vitro. We also demonstrated that the chimeric peptide persisted for 24 hours after transient delivery in the balloon-injured rat carotid artery. Treatment with the N-cadherin–targeting chimeric peptide reduced intimal thickening in balloon-injured rat carotid arteries at 1 and 2 weeks after injury. Reendothelialization of injured vessels after 2 weeks was unimpaired by peptide treatment. CONCLUSIONS: These studies show that an N-cadherin–binding and fibronectin-binding chimeric peptide is effective in inhibiting SMC migration in vitro and in vivo and limiting neointimal hyperplasia after balloon angioplasty without affecting EC repair. These results establish the potential of an advantageous SMC-selective strategy for antirestenosis therapy.