Nusrat Matin

The effects of hypertension on the cerebral circulation.

Maintenance of brain function depends on a constant blood supply. Deficits in cerebral blood flow are linked to cognitive decline, and they have detrimental effects on the outcome of ischemia. Hypertension causes alterations in cerebral artery structure and function that can impair blood flow, particularly during an ischemic insult or during periods of low arterial pressure. This review will focus on the historical discoveries, novel developments, and knowledge gaps in 1) hypertensive cerebral artery remodeling, 2) vascular function with emphasis on myogenic reactivity and endothelium-dependent dilation, and 3) blood-brain barrier function. Hypertensive artery remodeling results in reduction in the lumen diameter and an increase in the wall-to-lumen ratio in most cerebral arteries; this is linked to reduced blood flow postischemia and increased ischemic damage. Many factors that are increased in hypertension stimulate remodeling; these include the renin-angiotensin-aldosterone system and reactive oxygen species levels. Endothelial function, vital for endothelium-mediated dilation and regulation of myogenic reactivity, is impaired in hypertension. This is a consequence of alterations in vasodilator mechanisms involving nitric oxide, epoxyeicosatrienoic acids, and ion channels, including calcium-activated potassium channels and transient receptor potential vanilloid channel 4. Hypertension causes blood-brain barrier breakdown by mechanisms involving inflammation, oxidative stress, and vasoactive circulating molecules. This exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline, and impaired recovery from ischemia. As the population ages and the incidence of hypertension, stroke, and dementia increases, it is imperative that we gain a better understanding of the control of cerebral artery function in health and disease.

Rigid and remodelled: cerebrovascular structure and function after experimental high‐thoracic spinal cord transection

Spinal cord injury (SCI) is associated with a 3–4 fold increased risk of stroke, and impaired cerebral blood flow regulation, although the effect of SCI on the structure and function of the cerebral arteries is unclear. Using pressure myography to assess isolated vessels distended at physiological pressures, we provide novel evidence that experimental SCI leads to inward cerebrovascular remodelling, increased stiffness and impaired reactivity of the largest cerebral artery. Histochemical analyses revealed that a profibrotic environment within the largest cerebral artery occurs after SCI, which was characterized by greater collagen and less elastin. This may be due to increased transforming growth factor β, a well‐known profibrotic signalling protein. Further analysis revealed that profibrotic alterations were not due to disruption of descending sympathetic pathways to the cerebrovasculature. Experimental SCI exerts a deleterious influence on the structure and function of cerebral arteries, which may underlie the increased risk of stroke and impaired cerebral blood flow regulation.

The effects of obesity on the cerebral vasculature.

The incidence of obesity in the population is increasing at an alarming rate, with this comes an increased risk of insulin resistance (IR). Obesity and IR increase an individuals risk of having a stroke and they have been linked to several forms of dementia. Stroke and dementia are associated with, or exacerbated by, reduced cerebral blood flow, which has recently been described in obese patients. In this review we will discuss the effects of obesity on cerebral artery function and structure. Regarding their function, we will focus on the endothelium and nitric oxide (NO) dependent dilation. NO dependent dilation is impaired in cerebral arteries from obese rats, and the majority of evidence suggests this is a result of increased oxidative stress. We will also describe the limited studies showing that inward cerebral artery remodeling occurs in models of obesity, and that the remodeling is associated with an increase in the damage caused by cerebral ischemia. We will also discuss some of the more paradoxical findings associated with stroke and obesity, including the evidence that obesity is a positive factor for stroke survival. Finally we will discuss the evidence that links these changes in vascular structure and function to cognitive decline and dementia.

Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles

Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.

Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles

Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.

DOCA-salt hypertension impairs artery function in rat middle cerebral artery and parenchymal arterioles.

Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about PAs, which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of DOCA‐salt induced hypertension on endothelial function and artery structure in PAs and MCAs.