Arteries exhibit a remarkable ability to adapt to diverse genetic defects and sustained alterations in mechanical loading. For example, changes in blood flow induced wall shear stress tend to control arterial caliber and changes in blood pressure induced circumferential wall stress tend to control wall thickness. We submit, however, that the axial component of wall stress plays a similarly fundamental role in controlling arterial geometry, structure, and function, that is, compensatory adaptations. This observation comes from a review of findings reported in the literature and a comparison of four recent studies from our laboratory that quantified changes in the biaxial mechanical properties of mouse carotid arteries in cases of altered cell-matrix interactions, extracellular matrix composition, blood pressure, or axial extension. There is, therefore, a pressing need to include the fundamental role of axial wall stress in conceptual and theoretical models of arterial growth and remodeling and, consequently, there is a need for increased attention to evolving biaxial mechanical properties in cases of altered genetics and mechanical stimuli.

The structural protein elastin endows large arteries with unique biological functionality and mechanical integrity, hence its disorganization, fragmentation, or degradation can have important consequences on the progression and treatment of vascular diseases. There is, therefore, a need in arterial mechanics to move from materially uniform, phenomenological, constitutive relations for the wall to those that account for separate contributions of the primary structural constituents: elastin, fibrillar collagens, smooth muscle, and amorphous matrix. In this paper, we employ a recently proposed constrained mixture model of the arterial wall and show that prestretched elastin contributes significantly to both the retraction of arteries that is observed upon transection and the opening angle that follows the introduction of a radial cut in an unloaded segment. We also show that the transmural distributions of elastin and collagen, compressive stiffness of collagen, and smooth muscle tone play complementary roles. Axial prestresses and residual stresses in arteries contribute to the homeostatic state of stress in vivo as well as adaptations to perturbed loads, disease, or injury. Understanding better the development of and changes in wall stress due to individual extracellular matrix constituents thus promises to provide considerable clinically important insight into arterial health and disease.

Transgenic mouse models of Marfan Syndrome (MFS) provide insight into the type and extent of vascular abnormalities manifested in this disease. Inclusion of the mgR mutation causes the otherwise normal extracellular matrix protein fibrillin-1 to be under-expressed at ~25% of its normal value, a condition seen in MFS. Aortas in patients with MFS are generally less distensible and may experience dissecting aneurysms that lead to premature death. In this study, mouse carotid arteries heterozygous (mgR HET) and homozygous (mgR KO) for the mgR mutation were studied under biaxial loading and compared to wild-type controls (mgR WT). Carotids from WT and HET mice exhibited similar mechanical characteristics whereas those from KO mice were only slightly stiffer in the circumferential direction. The most significant difference in the KO arteries was primarily in the axial direction where axial stiffness was greater and the in vivo axial prestretch was less than in WT and HET counterparts. Stress-stretch data were fit by a four-fiber family constitutive model for each mouse genotype using the simplex method of parameter estimation where a lower value of a parameter typically ascribed to the elastin-dominated amorphous matrix. In conclusion, it appears that changes in axial mechanical properties may afford vessels a means to compensate, in part, for the loss of important structural constituents as they attempt to maintain mechanical homeostasis.

Arteries experience marked variations in blood pressure and flow during the cardiac cycle that can intensify during exercise, in disease, or with aging. Diverse observations increasingly suggest the importance of such pulsatility in arterial homeostasis and adaptations. We used a transverse aortic arch banding model to quantify chronic effects of increased pulsatile pressure and flow on wall morphology, composition, and biaxial mechanical properties in paired mouse arteries: the highly pulsatile right common carotid artery proximal to the band (RCCA-B) and the nearly normal left carotid artery distal to the band (LCCA-B). Increased pulsatile mechanical stimuli in RCCA-B increased wall thickness compared to LCCA-B, which correlated stronger with pulse (r*=0.632; p<0.01) than mean (r*=0.020; p=0.47) or systolic (r*=0.466; p<0.05) pressure. Similarly, inner diameter at mean pressure increased in RCCA-B and correlated slightly stronger with a normalized index of blood velocity pulsatility (r*=0.915; p≪0.001) than mean flow (r*=0.834; p<0.001). Increased wall thickness and luminal diameter in RCCA-B resulted from significant increases in cell number per cross-sectional area (p<0.001) and collagen to elastin ratio (p<0.05) as well as a moderate (1.7-fold) increase in glycosaminoglycan content, which appear to have contributed to the significant decrease (p<0.001) in the in vivo axial stretch in RCCA-B compared to LCCA-B. Changes in RCCA-B also associated with a signficant increase in monocyte chemoattractant protein-1 (p<0.05). Pulsatile pressure and flow are thus important stimuli in the observed three-dimensional arterial adaptations, and there is a need for increased attention to the roles of both axial wall stress and adventitial remodeling.

Cardiac valve structure and function are primarily determined during early development. Consequently, abnormally-formed heart valves are the most common type of congenital heart defects. Several adult valve diseases can be backtracked to abnormal valve development, making it imperative to completely understand the process and regulation of heart valve development. Epithelial-to-mesenchymal transition (EMT) plays an important role in the development of heart valves. Though hemodynamics is vital to valve development, its role in regulating EMT is still unknown. In this study, intracardiac hemodynamics were altered by constricting the outflow tract (OFT)/ventricle junction (OVJ) of HH16–17 (Hamilton and Hamburger (HH) Stage 16–17) chicken embryos, ex ovo for 24 h. The constriction created an increase in peak and time-averaged centerline velocity along the OFT without changes to volumetric flow or heart rate. Computational fluid dynamics was used to estimate the level of increased spatially-averaged wall shear stresses on the OFT cushion from AMIRA reconstructions. OFT constriction led to a significant decrease in OFT cushion volume and the number of invaded mesenchyme in the OFT cushion. qPCR analysis revealed altered mRNA expression of a representative panel of genes, vital to valve development, in the OFT cushions from banded hearts. This study indicates the importance of hemodynamics in valve development.