No abstract

Marfan syndrome (MFS) is a multi-system connective tissue disorder that results from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Although elastic fibers are compromised throughout the arterial tree, the most severe phenotype manifests in the ascending aorta. By comparing biaxial mechanics of the ascending and descending thoracic aorta in a mouse model of MFS, we show that aneurysmal propensity correlates well with both a marked increase in circumferential material stiffness and an increase in intramural shear stress despite a near maintenance of circumferential stress. This finding is corroborated via a comparison of the present results with previously reported findings for both the carotid artery from the same mouse model of MFS and for the thoracic aorta from another model of elastin-associated glycoprotein deficiency that does not predispose to thoracic aortic aneurysms. We submit that the unique biaxial loading of the ascending thoracic aorta conspires with fibrillin-1 deficiency to render this aortic segment vulnerable to aneurysm and rupture.

Purpose To delineate responses of optic nerve head astrocytes to sustained intraocular pressure (IOP) elevation in mice. Methods We elevated IOP for 1 day to 6 weeks by intracameral microbead injection in 4 strains of mice. Astrocyte alterations were studied by transmission electron microscopy (TEM) including immunogold molecular localization, and by laser scanning microscopy (LSM) with immunofluorescence for integrin β1, α-dystroglycan, and glial fibrillary acidic protein (GFAP). Astrocyte proliferation and apoptosis were quantified by Ki67 and TUNEL labeling, respectively. Results Astrocytes in normal optic nerve head expressed integrin β1 and α-dystroglycan by LSM and TEM immunogold labeling at electron dense junctional complexes that were found only on cell membrane zones bordering their basement membranes (BM) at the peripapillary sclera (PPS) and optic nerve head capillaries. At 1–3 days after IOP elevation, abnormal extracellular spaces appeared between astrocytes near PPS, and axonal vesical and mitochondrial accumulation indicated axonal transport blockade. By 1 week, abnormal spaces increased, new collagen formation occurred, and astrocytes separated from their BM, leaving cell membrane fragments. Electron dense junctional complexes separated or were absent at the BM. Astrocyte proliferation was modest during the first week, while only occasional apoptotic astrocytes were observed by TEM and TUNEL. Conclusions Astrocytes normally exhibit junctions with their BM which are disrupted by extended IOP elevation. Responses include reorientation of cell processes, new collagen formation, and cell proliferation.

Intramural cells are responsible for establishing, maintaining, and restoring the functional capability and structural integrity of the aortic wall. In response to hypertensive loading, these cells tend to increase wall content via extracellular matrix turnover in an attempt to return wall stress and/or material stiffness toward homeostatic values despite the elevated pressure. Using a common rodent model of induced hypertension, we found marked mouse-to-mouse differences in thoracic aortic remodeling over 2–4 wk of pressure elevation, with mechanoadaptation in some but gross maladaptation in most mice despite the same experimental conditions and overall genetic background. Consistent with our hypothesis, we also found a strong correlation between maladaptive aortic remodeling and a dysfunctional ability of the vessel to vasoconstrict, with maladaptation often evidenced by marked adventitial fibrosis. Remarkably, mouse-to-mouse variability did not correlate with the degree or duration of pressure elevation over the 2- to 4-wk study period. These findings suggest both a need to study together the structure, mechanical properties, and function across layers of the wall when assessing aortic health and a need for caution in using common statistical comparisons across small seemingly well-defined groups that may mask important underlying individual responses, an area of investigation that demands increasing attention as we move toward an era of precision diagnosis and patient care. NEW & NOTEWORTHY There are three primary findings. Marked mouse-to-mouse differences exist in large vessel hypertensive remodeling in an otherwise equivalent cohort of animals. The degree of maladaptation correlates strongly with decreases in smooth muscle contractile capacity. Finally, short-term maladaptive remodeling is independent of the precise degree or duration of the pressure elevation provided that thresholds are exceeded. Therapeutic targets should thus be personalized and focus on both layer-to-layer interactions and early interventions.

Objective Williams syndrome (WS) is characterized by obstructive aortopathy attributable to heterozygous loss of ELN, the gene encoding elastin. Lesions are thought to result primarily from excessive smooth muscle cell (SMC) proliferation and consequent medial expansion, although an initially smaller caliber and increased stiffness of the aorta may contribute to luminal narrowing. The relative contributions of such abnormalities to the obstructive phenotype had not been defined. Approach and Results We quantified determinants of luminal stenosis in thoracic aortas of Eln−/− mice incompletely rescued by human ELN. Moderate obstruction was largely due to deficient circumferential growth, most prominently of ascending segments, despite increased axial growth. Medial thickening was evident in these smaller diameter elastin-deficient aortas, with medial area similar to that of larger diameter control aortas. There was no difference in cross-sectional SMC number between mutant and wild-type genotypes at multiple stages of postnatal development. Decreased elastin content was associated with medial fibrosis and reduced aortic distensibility due to increased structural stiffness but preserved material stiffness. Elastin-deficient SMCs exhibited greater contractile-to-proliferative phenotypic modulation in vitro than in vivo. We confirmed increased medial collagen without evidence of increased medial area or SMC number in a small ascending aorta with thickened media of a WS subject. Conclusions Deficient circumferential growth is the predominant mechanism for moderate obstructive aortic disease resulting from partial elastin deficiency. Our findings suggest that diverse aortic manifestations in WS result from graded elastin content, and SMC hyperplasia causing medial expansion may require additional elastin loss superimposed on ELN haploinsufficiency.