Angiogenesis, which is the formation of new blood vessels from those pre-existing, occurs during development, wound healing, and tumor growth, and in response to stimuli such as exercise and hypoxia (1-3). This process involves complex signaling events that cause the endothelial cells comprising capillaries to initiate proliferative and migratory phenotypes. The sprouting endothelial cells must break through their existing basement membrane and form contacts with and migrate along different extracellular matrix components, finally establishing a new, patent capillary (1, 2).In an effort to define the molecular mechanisms underlying these events, a number of in vitro cell systems have been established. These include growth of endothelial cells or blood vessel fragments in fibrin clots, on amnionic membranes, in collagen matrices, and on Matrigel ® matrices (4-6). These models are characterized by re-organization that requires significant endothelial cell migration and/or invasion, and remodeling of the surrounding matrix molecules. It has been shown that microvascular endothelial cells undergo morphological changes that can include organization into tubelike structures when grown within a type I collagen matrix (7,8). The morphological changes are accompanied by changes in growth factor receptor profiles and extracellular matrix protein production (9, 10).Matrix metalloproteinases (MMPs) 1 belong to a family of enzymes with diverse substrate specificity, ranging from multiple extracellular matrix components to growth factors, cytokines, and other proteinases (11,12). It was first recognized that matrix metalloproteinases play a role in angiogenesis, based on the observation that inhibition of MMP activity by endogenous tissue inhibitors of metalloproteinases or synthetic compounds could inhibit in vitro tube formation (13,14). Several studies have demonstrated that the gelatinases, MMP-2 and MMP-9, are involved in vascular cell migration and invasion assays (15, 16). However, the regulation of MMP expression and activation during angiogenic events is not well understood. The recent cloning of several membrane-type MMPs (MT-MMPs) (17-19) that each contain a putative transmembrane domain and appear to have substrate specificity for the pro-MMP-2 has led to considerable speculation concerning the role of the cell surface in regulating proteolytic activity, and the extent to which MT-MMPs may be involved in controlling proteolytic cascades involving .We hypothesized that the controlled activation of metalloproteinases would be necessary for the in vitro remodeling of endothelial cells cultured in a collagen matrix, and that this activation would require the transcriptional up-regulation of specific MMPs, including MT-MMPs. Utilizing primary cultures of rat microvascular endothelial cells, we demonstrated a coordinate increase in expression of MMP-2 and MT1-MMP (MMP-14) following culture within a type I collagen matrix, and that activation of MMP-2 correlated temporally with MT1-MMP induction. MMP inhibitors blocked t...

No abstract

Proteolysis of the capillary basement membrane is a hallmark of inflammation-mediated angiogenesis, but it is undetermined whether proteolysis plays a critical role in the process of activity-induced angiogenesis. Matrix metalloproteinases (MMPs) constitute the major class of proteases responsible for degradation of basement membrane proteins. We observed significant elevations of mRNA and protein levels of both MMP-2 and membrane type 1 (MT1)-MMP (2.9 +/- 0.7- and 1.5 +/- 0.1-fold above control, respectively) after 3 days of chronic electrical stimulation of rat skeletal muscle. Inhibition of MMP activity via the inhibitor GM-6001 prevented the growth of new capillaries as assessed by the capillary-to-fiber ratio (1.34 +/- 0.08 in GM-6001-treated muscles compared with 1.69 +/- 0.03 in control 7-day-stimulated muscles). This inhibition correlated with a significant reduction in the number of capillaries with observable breaks in the basement membrane, as assessed by electron microscopy (0.27 +/- 0.27% in GM-6001-treated muscles compared with 3.72 +/- 0.65% in control stimulated muscles). Proliferation of capillary-associated cells was significantly elevated by 2 days and remained elevated throughout 14 days of stimulation. Capillary-associated cell proliferation during muscle stimulation was not affected by MMP inhibition (80.3 +/- 9.3 nuclei in control and 63.5 +/- 8.5 nuclei in GM-6001-treated animals). We conclude that MMP proteolysis of capillary basement membrane proteins is a critical component of physiological angiogenesis, and we postulate that capillary-associated proliferation precedes and occurs independently of endothelial cell sprout formation.

Matrix metalloproteinase activity is instrumental in processes of cellular invasion. The interstitial invasion of endothelial cells during angiogenesis is accompanied by up-regulation of several matrix metalloproteinases, including membrane type 1 matrix metalloproteinase (MT1-MMP). In this study, we show that endothelial cells stimulated to undergo angiogenesis by a three-dimensional extracellular matrix environment increase production of the transcription factor Egr-1. Increased binding of Egr-1 to the MT1-MMP promoter correlates with enhanced transcriptional activity, whereas mutations in the Egr-1 binding site abrogate the increased transcription of MT1-MMP in the stimulated cells. These data identify Egr-1-mediated transcription of MT1-MMP as a mechanism by which endothelial cells can initiate an invasive phenotype in response to an alteration in extracellular matrix environment, thus functionally associating MT1-MMP with a growing number of proteins known to be up-regulated by Egr-1 in response to tissue injury or mechanical stress.

In the past twenty years, the importance of the physical and social environments in supporting the person with dementia has gained a much higher profile in dementia care. Despite efforts to move aged care away from the medical model to a more balanced social model of care, we still struggle with the dominance of an institutional context which impedes individuality and choice. This article argues that the experience of the person with dementia should frame the perspective brought to built design and the philosophy of care -in essence, 'looking out from the inside'. Shifting the emphasis from condition to experience encourages the culture change needed to create environments that allow the person with dementia to be an active participant in everyday life rather than a passive recipient of care. Based on the development of a resource for residential and respite facilities in Australia, seven living experiences are identified: the presentation of self-experience, eating experience, personal enjoyment experience, bedroom experience, family and community connections experience, end-of-life experience and the staff experience. Each is discussed to show how consideration of the living experiences provides a way to focus thinking for design of the built environment to practically support the person with dementia, thereby addressing the wider spectrum of issues in creating a dementia friendly physical and social environment from the perspective of the person with dementia.Keywords dementia care; long-term care; person centred; physical environment; social environment de men tia d e m e n t i a

Platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31), a 130-kDa glycoprotein member of the Ig superfamily of transmembrane proteins, is expressed on endothelial cells, platelets, and subsets of leukocytes. It functions as a cell adhesion molecule as well as a scaffolding molecule capable of modulating cellular signaling pathways. In this study, using PECAM-1-deficient (KO) mice, as well as cells derived from these mice, we demonstrate that the absence of PECAM-1 expression is associated with an early onset of clinical symptoms during experimental autoimmune encephalomyelitis (EAE), a mouse model for the human autoimmune disease multiple sclerosis. During EAE, mononuclear cell extravasation and infiltration of the CNS occur at earlier time points in PECAM-KO mice than in wild-type mice. In vitro, T lymphocyte transendothelial migration across PECAM-KO endothelial cells is enhanced, regardless of expression of PECAM-1 on transmigrating T cells. Additionally, cultured PECAM-KO endothelial cells exhibit prolonged permeability changes in response to histamine treatment compared with PECAM-1-reconstituted endothelial cells. Lastly, we demonstrate an exaggerated and prolonged CNS vascular permeability during the development of EAE and a delay in restoration of dermal vascular integrity following histamine challenge in PECAM-KO mice.

Approximately 36% of the rural Australian population is 65 years and older. In fact, many rural and remote communities have higher proportions of older people than metropolitan centres. The rate of growth, patterns of migration, higher levels of health risk factors and of social and economic disadvantage all impact on rural healthy ageing. Older people in rural communities have become marginalized by longstanding misconceptions about rural life and urban-centric policies, much of which goes unchallenged because of a paucity of research in key areas and a lack of intrarural research. Understanding the complexities of rural healthy ageing is challenging, and more research is required to develop a stronger empirical base. The aim of this review is to critique the literature related to rural ageing in Australia to identify the issues and challenges for rural healthy ageing and implications for policy and practice.

No abstract