| Autor: |
Halvorson BD; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada., Bao Y; Department of Biomedical Engineering, University of Western Ontario, London, Ontario, Canada., Singh KK; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada., Frisbee SJ; Department of Pathology and Laboratory Medicine, University of Western Ontario, London, Ontario, Canada., Hachinski V; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada., Whitehead SN; Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada., Melling CWJ; Department of Kinesiology, University of Western Ontario, London, Ontario, Canada., Chantler PD; Division of Exercise Physiology, West Virginia University, Morgantown, West Virginia, United States., Goldman D; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada., Frisbee JC; Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada. |
| Abstrakt: |
Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A 2 (TxA 2 ). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA 2 production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease. NEW & NOTEWORTHY With clinical studies linking vascular disease risk to depressive symptom emergence, we used obese Zucker rats, a model of chronic metabolic disease, to identify potential mechanistic links between these two negative outcomes. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction, after increased vascular oxidant stress/inflammation and TxA 2 production. Anti-TxA 2 interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism. |
