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The Effects of Endocrine Dysfunction on the Cerebrovasculature and StrokeStroke is the third leading cause of death in the United States and the leading cause of disability among adults.1 According to the American Heart Association Heart Disease and Stroke 2008 Update,1 there is, on average, 1 stroke every 40 seconds in the United States, and every 3-4 minutes someone dies of a stroke. Furthermore, stroke is a major financial burden on the healthcare system, and its prevalence will only continue to increase as the prevalence of its risk factors continues to increase. These risk factors include but are not limited to hypertension, atherosclerosis, diabetes, smoking, and obesity. Currently, therapy for ischemic stroke is very limited. The only approach for acute treatment of ischemic stroke approved by the Food and Drug Administration is clot lysis with tissue plasminogen activator (tPA), based on findings from the National Institute of Neurological Disorders and Stroke recombinant tPA Stroke Study Group demonstrating improvement in clinical outcome with tPA therapy compared to placebo-control patients.2 Patients receiving tPA therapy showed improvements in neurological outcome 3 months after stroke compared to patients receiving placebo. However, the window of treatment for tPA is very small and only a small percentage (<10%) of eligible 2 patients receive therapy. Although efforts to develop safe and effective treatment options for stroke patients continue, a gap remains between promising findings from the bench and positive results in clinical trials. In light of this, it is especially important that research is also focused on gaining better understanding of mechanisms that lead to increased stroke occurrence and increased stroke damage in order to make progress in diminishing the occurrence of stroke.
Increasing Muscle Mass by Deletion of Myostatin Improves Metabolic and Vascular Function in Obese (db/db) MiceObesity is the major emerging risk factor in the disease burden of western cultures. Obesity significantly reduces both metabolic and cardiovascular function, most notably inducing a state of insulin resistance in the former case and impeding endothelial control of vascular function in the latter. Mechanisms underpinning these defects are poorly understood and interventional therapies remain few. Exercise is a powerful method to limit or improve obesity-associated diseases, improving metabolic syndrome markers and endothelial function in obese patients. The salutatory effects of exercise are multi-factorial and include increases in muscle size and quality, reduction in fat mass and alterations in the components of plasma milieu. The relationships between the physiologic changes induced by exercise and improvements in metabolic and cardiovascular function are poorly defined. Myostatin, a TGF-β family member, is secreted by muscle, limits muscle growth and stimulates adipose tissue accumulation. Thus deletion of myostatin permits a method of assessing whether a component of exercise, increases in muscle mass, has positive effects on metabolic and vascular function. While myostatin deletion can improve glucose tolerance, the mechanisms are unclear. Whether myostatin deletion improves endothelial function in obesity is also not clear. The overall goal of the current study was to determine if increasing muscle mass by deletion of myostatin improves metabolic and vascular function in obese (db/db) mice.
Vascular Protection by Angiotensin Receptor Antagonism Involves Differential VEGF Expression in Both Hemispheres after Experimental StrokeWe identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset