Decreased Elastic Energy Storage, Not Increased Material Stiffness, Characterizes Central Artery Dysfunction in Fibulin-5 Deficiency Independent of Sex

Abstract

Central artery stiffness has emerged over the past 15 years as a clinically significant indicator of cardiovascular function and initiator of disease. Loss of elastic fiber integrity is one of the primary contributors to increased arterial stiffening in aging, hypertension, and related conditions. Elastic fibers consist of an elastin core and multiple glycoproteins; hence defects in any of these constituents can adversely affect arterial wall mechanics. In this paper, we focus on mechanical consequences of the loss of fibulin-5, an elastin-associated glycoprotein involved in elastogenesis. Specifically, we compared the biaxial mechanical properties of five central arteries-the ascending thoracic aorta, descending thoracic aorta, suprarenal abdominal aorta, infrarenal abdominal aorta, and common carotid artery-from male and female wild-type and fibulin-5 deficient mice. Results revealed that, independent of sex, all five regions in the fibulin-5 deficient mice manifested a marked increase in structural stiffness but also a marked decrease in elastic energy storage and typically an increase in energy dissipation, with all differences being most dramatic in the ascending and abdominal aortas. Given that the primary function of large arteries is to store elastic energy during systole and to use this energy during diastole to work on the blood, fibulin-5 deficiency results in a widespread diminishment of central artery function that can have significant effects on hemodynamics and cardiac function.

Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-β Signaling Despite Compromised Extracellular Matrix Properties

“…Consistent with data in Figure 2 and with respect to controls, iso-energetic contours were compressed along the ordinate (indicating lower distensibility) for ATAs and especially along the abscissa (indicating lower extensiblity) for DTAs for both the Tmx and Tmx+Rapa groups. Albeit not shown, control ATAs and DTAs displayed similar energy storage and degrees of anisotropy as wild-type mice 12 . Importantly, the reduced overall energy stored elastically in ATAs and DTAs of mice with Tgfbr2 disruption compromises their primary mechanical function (i.e., storage of elastic energy during systole that can be used to work on the blood during diastole to augment flow), and rapamycin neither prevented this reduction nor restored it towards normal (it actually worsened it in the DTA).…”

“…Indeed, rapamycin did not protect against or reverse the marked changes in passive biaxial properties, which may require adequate synthesis of ECM to ensure structural integrity. Tgfbr2 disruption, with or without treatment with rapamycin, resulted in a significant decrease in elastic energy storage (Figure 3), which marks decreased mechanical functionality 12 . Although circumferential material stiffness was not affected significantly by Tgfbr2 disruption, or its treatment with rapamycin, there was a trend in the ATA and significance in the DTA toward a decrease in the passive in vivo axial stretch (Figure 2), which likely contributed to the overall decreases in wall stress (Figure 2).…”

Excessive Adventitial Remodeling Leads to Early Aortic Maladaptation in Angiotensin-Induced Hypertension

“…A consequence of these differential responses is a dramatically reduced ability of the aorta to store elastic energy during systole (Figure 1F), which compromises its primary mechanical function to sustain blood flow during diastole. 1,3,14 …”

Differential ascending and descending aortic mechanics parallel aneurysmal propensity in a mouse model of Marfan syndrome

“…Male mice homozygous for a hypomorphic allele of the fibrillin-1 gene ( Fbn1 mgR/mgR ) and wild-type ( WT ) littermate controls were euthanized between 8 and 9 weeks of age and the thoracic aorta was excised. Details on our methods of biaxial testing and data analysis are given elsewhere (Bellini et al, 2015; Ferruzzi et al, 2015). Briefly, each vessel was cleaned of peri-adventitial tissue and divided into two segments: the ascending thoracic aorta (ATA), extending from the aortic root to the brachiocephalic artery, and the descending thoracic aorta (DTA), extending from the left subclavian artery to the third pair of intercostal arteries.…”