Cardiovascular function and structure are preserved despite induced ablation of BMP1-related proteinases.

INTRODUCTION: Bone morphogenetic protein 1 (BMP1) is part of an extracellular metalloproteinase family that biosynthetically processes procollagen molecules. BMP1- and tolloid-like (TLL1) proteinases mediate the cleavage of carboxyl peptides from procollagen molecules, which is a crucial step in fibrillar collagen synthesis. Ablating the genes that encode BMP1-related proteinases (Bmp1 and Tll1) post-natally results in brittle bones, periodontal defects, and thin skin in conditional knockout (BTKO) mice. Despite the importance of collagen to cardiovascular tissues and the adverse effects of Bmp1 and Tll1 ablation in other tissues, the impact of Bmp1 and Tll1 ablation on cardiovascular performance is unknown. Here, we investigated the role of Bmp1- and Tll1-ablation in cardiovascular tissues by examining ventricular and vascular structure and function in BTKO mice. METHODS: Ventricular and vascular structure and function were comprehensively quantified in BTKO mice (n=9) and in age- and sex-matched controls (n=9). Echocardiography, cardiac catheterization, and biaxial ex vivo arterial mechanical testing were performed to assess tissue function, and histological staining was used to measure collagen protein content. RESULTS: Bmp1- and Tll1-ablation resulted in maintained hemodynamics and cardiovascular function, preserved biaxial arterial compliance, and comparable ventricular and vascular collagen protein content. CONCLUSIONS: Maintained ventricular and vascular structure and function despite post-natal ablation of Bmp1 and Tll1 suggests that there is an as-yet unidentified compensatory mechanism in cardiovascular tissues. In addition, these findings suggest that proteinases derived from Bmp1 and Tll1 post-natally have less of an impact on cardiovascular tissues compared to skeletal, periodontal, and dermal tissues.

Pulmonary arterial strain- and remodeling-induced stiffening are differentiated in a chronic model of pulmonary hypertension.

Pulmonary hypertension (PH) is a debilitating vascular disease that leads to pulmonary artery (PA) stiffening, which is a predictor of patient mortality. During PH development, PA stiffening adversely affects right ventricular function. PA stiffening has been investigated through the arterial nonlinear elastic response during mechanical testing using a canine PH model. However, only circumferential properties were reported and in the absence of chronic PH-induced PA remodeling. Remodeling can alter arterial nonlinear elastic properties via chronic changes in extracellular matrix (ECM) content and geometry. Here, we used an established constitutive model to demonstrate and differentiate between strain-stiffening, which is due to nonlinear elasticity, and remodeling-induced stiffening, which is due to ECM and geometric changes, in a canine model of chronic thromboembolic PH (CTEPH). To do this, circumferential and axial tissue strips of large extralobar PAs from control and CTEPH tissues were tested in uniaxial tension, and data were fit to a phenomenological constitutive model. Strain-induced stiffening was evident from mechanical testing as nonlinear elasticity in both directions and computationally by a high correlation coefficient between the mechanical data and model (R2=0.89). Remodeling-induced stiffening was evident from a significant increase in the constitutive model stress parameter, which correlated with increased PA collagen content and decreased PA elastin content as measured histologically. The ability to differentiate between strain- and remodeling-induced stiffening in vivo may lead to tailored clinical treatments for PA stiffening in PH patients.