Obese/overweight patients have an increased risk of developing cognitive impairments that can lead to dementia. This is a major public health concern because the majority of the adult population is overweight or obese. Overweight individuals have reduced cerebral perfusion and this can cause impaired cognition; the cause of this cerebral hypoperfusion is unknown. This is an important knowledge gap; understanding the cause of the hypoperfusion is key to identifying therapeutic targets to slow or prevent cognitive decline in a society plagued by obesity. The parenchymal arterioles (PAs) connect the pial and capillary networks and regulate the perfusion of the brain parenchyma. Our preliminary data show that endothelium dependent dilation is markedly impaired in PAs from overweight rats and these rats develop cognitive dysfunction. Despite their importance in regulating brain perfusion, little is known about PA function in health and disease. Dilation in PAs relies heavily on intracellular calcium (Ca2+) signaling, and Ca2+ influx through transient receptor potential (TRP) channels is an important mediator of cerebral artery endothelium dependent dilation. We showed that activation of the vanilloid 4 TRP channel (TRPV4) causes PA dilation. Preliminary studies show that TRPV4 expression is reduced in overweight rats and this is linked to mineralocorticoid receptor activation. Circulating levels of the mineralocorticoid aldosterone are increased in overweight patients and in our rat and mouse models. Our hypothesis is that MR activation in PA endothelial cells leads to reduced TRPV4 expression, impaired endothelium-dependent dilation, cerebral hypoperfusion and cognitive impairment in overweight rats. We will utilize a combination of in vivo and in vitro techniques including MRI, confocal microscopy, electrophysiology and pressure myography to test our hypothesis. We will determine how excess adiposity impairs PA function, cerebral perfusion, and cognition. Our working hypothesis is that TRPV4 expression is reduced in overweight rats and that this leads to impaired Ca2+-mediated endothelium-dependent dilation in PAs and is associated with reduced cerebral perfusion and impaired cognition. We further propose that directly inhibiting TRPV4 will cause cerebral hypoperfusion and cognitive decline. We will also determine the effects of MR activation on PA function, cerebral perfusion, and cognition. Our working hypothesis is that MR activation in PA endothelial cells causes reduced TRPV4 expression, impaired Ca2+ mediated dilation, cerebral hypoperfusion and cognitive decline. We further propose that MR antagonism in overweight rats will improve PA function in a TRPV4 dependent manner and that this will lead to improved cerebral perfusion and cognitive function. The MR is a highly drugable target, MR antagonists are safe, effective FDA approved drugs. Their use in the overweight/obese population could dramatically reduce the burden on families and the healthcare system that occurs when patients become too cognitively impaired to live independently.
Overweight/obese patients are at an increased risk of developing hyperaldosteronism and cognitive impairments that can lead to dementia; we do not know if these two conditions are linked. We propose that aldosterone, or mineralocorticoid receptor activation, reduces the calcium mediated endothelium dependent dilation in cerebral parenchymal arterioles to produce a chronic state of mild cerebral hypoperfusion, which leads to vascular cognitive impairment. Our studies will utilize models of high fat feeding that are analogous to an overweight adults who began overeating as a children, allowing us to evaluate a clinically relevant problem: the majority of overweight children become overweight adults and we do not know how this ?life-long? obesity affects the cerebral arteries.
| Pires, Paulo W; McClain, Jonathon L; Hayoz, Sebastian F et al. (2018) Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats. Microcirculation 25:e12460 |
| Diaz-Otero, Janice Marie; Yen, Ting-Chieh; Fisher, Courtney et al. (2018) Mineralocorticoid Receptor Antagonism Improves Parenchymal Arteriole Dilation Via a TRPV4-Dependent Mechanism and Prevents Cognitive Dysfunction in Hypertension. Am J Physiol Heart Circ Physiol : |
| Matin, Nusrat; Fisher, Courtney; Jackson, William F et al. (2018) Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles. Am J Physiol Heart Circ Physiol 314:H122-H130 |
| Diaz-Otero, Janice M; Fisher, Courtney; Downs, Kelsey et al. (2017) Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension. Hypertension 70:1113-1121 |
