Early elevations in arterial pressure: a contributor to rapid depressive symptom emergence in female Zucker rats with metabolic disease?

One of the growing challenges to public health and clinical outcomes is the emergence of cognitive impairments, particularly depressive symptom severity, because of chronic elevations in metabolic disease and cerebrovascular disease risk. To more clearly delineate these relationships and to assess the potential for sexual dimorphism, we used lean (LZR) and obese Zucker rats (OZR) of increasing age to determine relationships between internal carotid artery (ICA) hemodynamics, cerebral vasculopathies, and the emergence of depressive symptoms. Male OZR exhibited progressive elevations in perfusion pressure within the ICA, which were paralleled by endothelial dysfunction, increased cerebral arterial myogenic activation, and reduced cerebral cortex microvessel density. In contrast, female OZR exhibited a greater degree of ICA hypertension than male OZR but maintained normal endothelial function, myogenic activation, and microvessel density to an older age range than did males. Although both male and female OZR exhibited significant and progressive elevations in depressive symptom severity, these were significantly worse in females. Finally, plasma cortisol concentration was elevated higher and at a younger age in female OZR as compared with males, and this difference was maintained to final animal usage at ∼17 wk of age. These results suggest that an increased severity of blood pressure waves may penetrate the cerebral circulation more deeply in female OZR than in males, which may predispose the females to a more severe emergence of depressive symptoms with chronic metabolic disease, whereas males may be more predisposed to more direct cerebral vasculopathies (e.g., stroke, transient ischemic attack). We provide novel insight that the superior maintenance of cerebrovascular endothelial function in female versus male rats with chronic metabolic disease buffers myogenic activation of cerebral resistance arteries/arterioles despite worsening hypertension. As hypertension development is earlier and more severe in females, potentially due to an elevated stress response, the blunted myogenic activation allows greater arterial pressure wave penetrance into the cerebral microcirculation and is associated with accelerated emergence/severity of depressive symptoms in obese female rats.