Progressive Development of Aberrant Smooth Muscle Cell Phenotype in Abdominal Aortic Aneurysm Disease

Abdominal aortic aneurysm (AAA) is a silent, progressive disease with a high mortality and an increasing prevalence with aging. Smooth muscle cell (SMC) dysfunction contributes to gradual dilatation and eventual rupture of the aorta. Here we studied phenotypic characteristics in SMC cultured from end-stage human AAA (≥5 cm) and cells cultured from a porcine carotid artery (PCA) model of early and end-stage aneurysm. Human AAA-SMC presented a secretory phenotype and expressed elevated levels of the differentiation marker miR-145 (2.2-fold, p < 0.001) and the senescence marker SIRT-1 (1.3-fold, p < 0.05), features not recapitulated in aneurysmal PCA-SMC. Human and end-stage porcine aneurysmal cells were frequently multi-nucleated (3.9-fold, p < 0.001, and 1.8-fold, p < 0.01, respectively, vs. control cells) and displayed an aberrant nuclear morphology. Human AAA-SMC exhibited higher levels of the DNA damage marker γH2AX (3.9-fold, p < 0.01, vs. control SMC). These features did not correlate with patients' chronological age and are therefore potential markers for pathological premature vascular aging. Early-stage PCA-SMC (control and aneurysmal) were indistinguishable from one another across all parameters. The principal limitation of human studies is tissue availability only at the end stage of the disease. Refinement of a porcine bioreactor model would facilitate the study of temporal modulation of SMC behaviour during aneurysm development and potentially identify therapeutic targets to limit AAA progression

Preservation of Smooth Muscle Cell Integrity and Function: A Target for Limiting Abdominal Aortic Aneurysm Expansion?

(1) Abdominal aortic aneurysm (AAA) is a silent, progressive disease with significant mortality from rupture. Whilst screening programmes are now able to detect this pathology early in its development, no therapeutic intervention has yet been identified to halt or retard aortic expansion. The inability to obtain aortic tissue from humans at early stages has created a necessity for laboratory models, yet it is essential to create a timeline of events from EARLY to END stage AAA progression. (2) We used a previously validated ex vivo porcine bioreactor model pre-treated with protease enzyme to create “aneurysm” tissue. Mechanical properties, histological changes in the intact vessel wall, and phenotype/function of vascular smooth muscle cells (SMC) cultured from the same vessels were investigated. (3) The principal finding was significant hyperproliferation of SMC from EARLY stage vessels, but without obvious histological or SMC aberrancies. END stage tissue exhibited histological loss of α-smooth muscle actin and elastin; mechanical impairment; and, in SMC, multiple indications of senescence. (4) Aortic SMC may offer a therapeutic target for intervention, although detailed studies incorporating intervening time points between EARLY and END stage are required. Such investigations may reveal mechanisms of SMC dysfunction in AAA development and hence a therapeutic window during which SMC differentiation could be preserved or reinstated

The Gene Ontology resource: enriching a GOld mine

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20 000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations

Structural and functional brain reorganisation due to blindness: The special case of bilateral congenital anophthalmia

Investigating the changes in the brain that result from a loss of sensory input has provided significant insight into the considerable capacity of the brain to reorganise. One of the difficulties in studying sensory-deprived populations is that the time and extent of sensory loss vary significantly. In this review, we consider the changes in the human brain associated with complete absence of visual input resulting from bilateral congenital anophthalmia, in which the eyes fail to develop. We describe the functional reorganisation and associated structural and connectivity changes that occur in the brain of those affected by the condition. By considering animal models of this condition, we investigate the changes that may be occurring on a scale that is not captured by human in vivo imaging techniques. Finally, we lay out a model pathway for taking auditory information to the occipital cortex that may be specific to anophthalmia

Language and nonverbal auditory processing in the occipital cortex of individuals who are congenitally blind due to anophthalmia

Individuals with congenital blindness due to bilateral anophthalmia offer a unique opportunity to examine cross-modal plasticity in the complete absence of any stimulation of the ‘visual’ pathway even during development in utero. Our previous work has suggested that this complete sensory deafferentation results in different patterns of reorganisation compared with those seen in other early blind populations. Here, we further test the functional specialisation of occipital cortex in six well-studied cases with anophthalmia. Whole brain functional MRI was obtained while these human participants and a group of sighted controls performed two experiments involving phonological and semantic processing of words (verbal experiment) and spatial and identity processing of piano chords (nonverbal experiment). Both experiments were predicted to show a dorsal-ventral difference in activity based on the specific task performed. All tasks evoked activation in occipital cortex in the individuals with anophthalmia but not in the sighted controls. For the verbal experiment, both dorsal and ventral occipital areas were strongly activated by the phonological and semantic tasks in anophthalmia. For the nonverbal experiment, both the spatial and the identity task robustly activated the dorsal occipital area V3a but showed inconsistent activity elsewhere in the occipital lobe. V1 was most strongly activated by the verbal tasks, showing greater activity on the left for the verbal task relative to the nonverbal one. For individual anophthalmic participants, however, activity in V1 was inconsistent across tasks and hemispheres with many participants showing activity levels in the control range, which was not significantly above baseline. Despite the homogeneous nature of the cause of blindness in the anophthalmic group, there remain differences in patterns of activation among the individuals with this condition. Investigation at the case level might further our understanding of how post-natal experiences shape functional reorganisation in deafferented cortex

Early auditory processing in area V5/MT+ of the congenitally blind brain.

Previous imaging studies of congenital blindness have studied individuals with heterogeneous causes of blindness, which may influence the nature and extent of cross-modal plasticity. Here, we scanned a homogeneous group of blind people with bilateral congenital anophthalmia, a condition in which both eyes fail to develop, and, as a result, the visual pathway is not stimulated by either light or retinal waves. This model of congenital blindness presents an opportunity to investigate the effects of very early visual deafferentation on the functional organization of the brain. In anophthalmic animals, the occipital cortex receives direct subcortical auditory input. We hypothesized that this pattern of subcortical reorganization ought to result in a topographic mapping of auditory frequency information in the occipital cortex of anophthalmic people. Using functional MRI, we examined auditory-evoked activity to pure tones of high, medium, and low frequencies. Activity in the superior temporal cortex was significantly reduced in anophthalmic compared with sighted participants. In the occipital cortex, a region corresponding to the cytoarchitectural area V5/MT+ was activated in the anophthalmic participants but not in sighted controls. Whereas previous studies in the blind indicate that this cortical area is activated to auditory motion, our data show it is also active for trains of pure tone stimuli and in some anophthalmic participants shows a topographic mapping (tonotopy). Therefore, this region appears to be performing early sensory processing, possibly served by direct subcortical input from the pulvinar to V5/MT+