Dysfunction in elastic fiber formation in fibulin-5 null mice abrogates the evolution in mechanical response of carotid arteries during maturation

Abstract

Wan W, Gleason RL, Jr. Dysfunction in elastic fiber formation in fibulin-5 null mice abrogates the evolution in mechanical response of carotid arteries during maturation. Am J Physiol Heart Circ Physiol 304: H674 -H686, 2013. First published December 15, 2012 doi:10.1152/ajpheart.00459.2012.-Elastin fragmentation is a common characteristic of vascular diseases, such as abdominal aortic aneurysms, peripheral arterial disease, and aortic dissection. Examining growth and remodeling in the presence of dysfunctional elastic fibers provides insight into the adaptive or maladaptive changes that tissues undergo in compensating for structural deficiencies. This study used the maturation of fibulin-5 knockout (KO) and wild-type mice to study the effects of fragmented elastic fibers on the growth and remodeling of carotid arteries. The microstructural content and organization and the biaxial mechanical behavior of common carotid arteries were measured, and parameter estimation performed from KO and WT mice aged 3, 4, 8, and 13 wk. Gross measurements and biaxial tests revealed significant differences in pressure-diameter behavior, in vivo axial stretch, opening angle, compliance, and wall stresses during maturation of wild-type arteries, but little change in these values in KO mice. Multiphoton microscopy used to image collagen fibers across the vessel wall in pressurized and stretched arteries suggests that there is little variation in fiber angles between different ages. Parameter estimation revealed significant differences in material parameters between genotypes and age groups. This study suggests that neonatal formation and cross-linking of functional elastic fibers, followed by increases in artery size due to growth with little remodeling of the elastic fibers, endow arteries with large distensibility and contribute to the evolution of mechanical behavior of arteries during maturation. Dysfunction in neonatal formation of elastic fibers abrogates many of the changes in mechanical response that take place during the maturation. artery mechanics; extracellular matrix; elastin; arterial stiffening; fbln5 LOSS OF FUNCTIONAL ELASTIC fibers is associated with various vascular diseases, including abdominal aortic aneurysms (5, 46), peripheral arterial disease (42, 43), aortic dissection (30, 49), as well as pathologies in other organ systems (13,20). Fibulin-5 (fbln5) is an extracellular matrix protein that binds to integrins and localizes tropoelastin to microfibrils (39, 62). In humans, altered expression of fbln5 is correlated with a variety of diseases, such as thoracic aortic dissection (59), age-related macular degeneration (52), as well as various cancers (26,36,63). Fbln5 knockout (KO) mice exhibit loose skin, pelvic organ prolapse, and tortuous arteries with disrupted elastic lamellae (39,62). Previous studies have shown that arteries from adult fbln5 KO mice have altered biomechanical and microstructural properties, including disrupted and dysfunctional elastic lamellae (58); however, evolution of biomechanical an...

Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

“…IVSR varies with location in the vascular tree (28,30) and age (84). Our data confirm that locational differences exist in newborn Fbln4 ϩ/ϩ mice and are consistent with previous observations.…”

Mechanical factors direct mouse aortic remodelling during early maturation

“…This is consistent with previous data on Fbln52/2 carotid arteries [13,14] and in contrast to [20]. Stresses and the stretch ratio were calculated from the mechanical test data and unloaded dimensions.…”

“…The values were determined using the fitted material constants and the stretch ratios corresponding to the mean physiologic blood pressure and the in vivo axial stretch for each artery. The trends for the stresses and the circumferential (circ) modulus are consistent with the experimental data in figure 3 Wan et al [14] also found a trend towards reduced elastin mass fractions in Fbln52/2 carotid arteries compared with WT. Yanagisawa et al [12] found a decrease in desmosine, an elastin-specific cross-link, in three-month-old Fbln52/2 aorta compared with WT and show electron micrographs with elastin aggregates in Fbln52/2 aorta, compared to complete elastic laminae in WT, that are consistent with our imaging results.…”

“…Although the dimensions do not change in the circumferential and radial direction, the Fbln52/2 aorta is longer than WT at all time points. This is consistent with lengthening observed in Elnþ/2 mice [7] and Fbln4SMKO mice [38] and with the reduced axial stretch ratios observed in fibrillin-1 insufficient mice (mgR) [39] and adult Fbln52/2 mice [13,14]. Because reduced axial stretch affects both circumferential and axial stress, it has been speculated that this may be a mechanism to maintain stress values despite changing material properties [40].…”

“…Wan et al [13,14] found the circumferential stress to be reduced in Fbln52/2 carotid artery compared with WT from four to13 weeks of age, but not at three weeks of age. However, the stresses in Wan et al [13,14] were calculated based on mean adult pressure values of 110 mmHg [12] for all ages, while our values are calculated from mean pressures at each age [20]. In figure 3c, the circumferential stresses diverge between genotypes just above the physiologic values for P21 and P60 aorta, highlighting the importance of determining the physiologic loading environment for relevant comparisons.…”