Biomechanical Regulation of Mesenchymal Stem Cells for Cardiovascular Tissue Engineering.

Mesenchymal stem cells (MSCs) are an appealing potential therapy for vascular diseases; however, many challenges remain in their clinical translation. While the use of biochemical, pharmacological, and substrate-mediated treatments to condition MSCs has been subjected to intense investigation, there has been far less exploration of using these treatments in combination with applied mechanical force for conditioning MSCs toward vascular phenotypes. This review summarizes the current understanding of the use of applied mechanical forces to differentiate MSCs into vascular cells and enhance their therapeutic potential for cardiovascular disease.

Critical buckling pressure in mouse carotid arteries with altered elastic fibers.

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.

Mechanical factors direct mouse aortic remodelling during early maturation.

Numerous diseases have been linked to genetic mutations that lead to reduced amounts or disorganization of arterial elastic fibres. Previous work has shown that mice with reduced amounts of elastin (Eln+/-) are able to live a normal lifespan through cardiovascular adaptations, including changes in haemodynamic stresses, arterial geometry and arterial wall mechanics. It is not known if the timeline and presence of these adaptations are consistent in other mouse models of elastic fibre disease, such as those caused by the absence of fibulin-5 expression (Fbln5-/-).

Fibulin-5 null mice with decreased arterial compliance maintain normal systolic left ventricular function, but not diastolic function during maturation.

Abstract The large arteries serve as compliant vessels that store energy during systole and return it during diastole. This function is made possible by the elastic fibers in the arterial wall that are assembled during late embryonic and early postnatal development from various proteins, including fibulin-5. Mice and humans with insufficient amounts of fibulin-5 have reduced arterial compliance as adults.

Measuring, reversing, and modeling the mechanical changes due to the absence of Fibulin-4 in mouse arteries.

Mice with a smooth muscle cell (SMC)-specific deletion of Fibulin-4 (SMKO) show decreased expression of SMC contractile genes, decreased circumferential compliance, and develop aneurysms in the ascending aorta. Neonatal administration of drugs that inhibit the angiotensin II pathway encourages the expression of contractile genes and prevents aneurysm development, but does not increase compliance in SMKO aorta. We hypothesized that multidimensional mechanical changes in the aorta and/or other elastic arteries may contribute to aneurysm pathophysiology.

Echocardiographic Characterization of Postnatal Development in Mice with Reduced Arterial Elasticity.

Purpose: Decreased expression of elastin results in smaller, less compliant arteries and high blood pressure. In mice, these differences become more significant with postnatal development. It is known that arterial size and compliance directly affect cardiac function, but the temporal changes in cardiac function have not been investigated in elastin insufficient mice.

Angiotensin-converting enzyme-induced activation of local angiotensin signaling is required for ascending aortic aneurysms in fibulin-4-deficient mice.

Aortic aneurysms are life-threatening and often associated with defects in connective tissues and mutations in smooth muscle cell (SMC) contractile proteins. Despite recent advances in understanding altered signaling in aneurysms of Marfan syndrome, the underlying mechanisms and options for pharmacological treatment for other forms of aneurysms are still under investigation. We previously showed in mice that deficiency in the fibulin-4 gene in vascular SMCs (Fbln4(SMKO)) leads to loss of the SMC contractile phenotype, hyperproliferation, and ascending aortic aneurysms.

Measuring left ventricular pressure in late embryonic and neonatal mice.

Blood pressure increases significantly during embryonic and postnatal development in vertebrate animals. In the mouse, blood flow is first detectable around embryonic day (E) 8.5(1).

Mechanical testing of mouse carotid arteries: from newborn to adult.

The large conducting arteries in vertebrates are composed of a specialized extracellular matrix designed to provide pulse dampening and reduce the work performed by the heart. The mix of matrix proteins determines the passive mechanical properties of the arterial wall(1). When the matrix proteins are altered in development, aging, disease or injury, the arterial wall remodels, changing the mechanical properties and leading to subsequent cardiac adaptation(2).

Effect of storage duration on the mechanical behavior of mouse carotid artery.

Determining arterial mechanical properties is important for understanding the work done by the heart and how it changes with cardiovascular disease. Ex vivo tests are necessary to apply various loads to the artery and obtain data to model and predict the behavior under any load. Most ex vivo tests are performed within 24 h of dissection, so the tissue is still "alive.

Decreased aortic diameter and compliance precedes blood pressure increases in postnatal development of elastin-insufficient mice.

Increased arterial stiffness and blood pressure are characteristic of humans and adult mice with reduced elastin levels caused by aging or genetic disease. Direct associations have been shown between increased arterial stiffness and hypertension in humans, but it is not known whether changes in mechanical properties or increased blood pressure occur first. Using genetically modified mice with elastin haploinsufficiency (Eln(+/-)), we investigated the temporal relationship between arterial mechanical properties and blood pressure throughout postnatal development.