Multimodal Imaging in Rats Reveals Impaired Neurovascular Coupling in Sustained Hypertension

Abstract

Background and Purpose-Arterial hypertension is an important risk factor for cerebrovascular diseases, such as transient ischemic attacks or stroke, and represents a major global health issue. The effects of hypertension on cerebral blood flow, particularly at the microvascular level, remain unknown. Methods-Using the spontaneously hypertensive rat (SHR) model, we examined cortical hemodynamic responses on whisker stimulation applying a multimodal imaging approach (multiwavelength spectroscopy, laser speckle imaging, and 2-photon microscopy). We assessed the effects of hypertension in 10-, 20-, and 40-week-old male SHRs and age-matched male Wistar Kyoto rats (CTRL) on hemodynamic responses, histology, and biochemical parameters. In 40-week-old animals, losartan or verapamil was administered for 10 weeks to test the reversibility of hypertensioninduced impairments. Results-Increased arterial blood pressure was associated with a progressive impairment in functional hyperemia in 20-and 40-week-old SHRs; baseline capillary red blood cell velocity was increased in 40-week-old SHRs compared with age-matched CTRLs. Antihypertensive treatment reduced baseline capillary cerebral blood flow almost to CTRL values, whereas functional hyperemic signals did not improve after 10 weeks of drug therapy. Structural analyses of the microvascular network revealed no differences between normo-and hypertensive animals, whereas expression analyses of cerebral lysates showed signs of increased oxidative stress and signs of impaired endothelial homeostasis upon early hypertension. Conclusions-Impaired neurovascular coupling in the SHR evolves upon sustained hypertension. Antihypertensive monotherapy using verapamil or losartan is not sufficient to abolish this functional impairment. These deficits in neurovascular coupling in response to sustained hypertension might contribute to accelerate progression of neurodegenerative diseases in chronic hypertension.

Laser speckle analysis synchronised with cardiac cycle

“…The observed blood flow changes as shown in Figure 8 are typical for functional activation experiments -showing a drop in contrast following the onset of activation and a single pronounced minimum followed by relaxation 10 . Change in signal of the SHR animals was lower compared with the control group, confirming previously reported findings 11 .…”

Enhanced Parenchymal Arteriole Tone and Astrocyte Signaling Protect Neurovascular Coupling Mediated Parenchymal Arteriole Vasodilation in the Spontaneously Hypertensive Rat

“…Given that we observed no EFS-induced NVC impairments at the level of the PAs in SHR, we propose that hypertension triggers adaptive responses in the brain parenchyma. In the absence of these adaptive responses, it is likely that FH impairments observed during hypertension [6][7][8][9] would be much more pronounced resulting in more profound consequences such as parenchymal ischemia. In light of these findings, future work should be directed towards determining whether global impairments in NVC responses are caused by inherent pial arteriole dysfunction, impaired upstream conduction of NVC signals, or a combination of both.…”

“…During the orchestrated signaling among neurons, astrocytes, and the cerebral vasculature that occurs during NVC-mediated vasodilation, synaptically released glutamate binds to astrocytic metabotropic glutamate receptors (mGluR) increasing intracellular Ca 2+ , 1,4 which, in turn, results in the release of vasoactive signals such as arachidonic acid (AA) metabolites 4 and K + . 5 Although FH is impaired in hypertensive patients and animal models of hypertension, [6][7][8][9] the mechanisms by which hypertension disrupts NVC among cells in the neurovascular unit is not fully understood. A few elegantly designed studies, primarily evaluating pial arteriole function, have used regional CBF measurements to deliver valuable insight into the vascular mechanisms underlying NVC disruptions during acute, short-term Angiotensin II-induced hypertension 6,9 and chronic hypertension.…”

“…A few elegantly designed studies, primarily evaluating pial arteriole function, have used regional CBF measurements to deliver valuable insight into the vascular mechanisms underlying NVC disruptions during acute, short-term Angiotensin II-induced hypertension 6,9 and chronic hypertension. 8 However, the effects of hypertension on NVC-mediated vasodilations have yet to be investigated solely in the distinct subpopulation of cerebral microvessels penetrating the brain parenchyma, the parenchymal arterioles (PAs). Given that artery size is an important determinant of cerebral myogenic responses 10 and that myogenic tone is mediated by different mechanisms in pial arterioles versus PAs, 11,12 the importance of studying hypertension-induced brain pathologies in discrete vascular beds should not be underestimated.…”

Response to Letter Regarding Article, “Relative Contributions of Sympathetic, Cholinergic, and Myogenic Mechanisms to Cerebral Autoregulation”

“…5 Thus, any impairment in extrinsic mechanisms that regulate pial arterial responses may affect metabolic responses, and vice versa. For example, some data suggest that neurovascular coupling may be impaired as a consequence of sustained hypertension, 6 and given that hypertension is associated with peripheral sympathetic overactivity, reduced ability of pial vessels to dilate may partly underlie impaired neurovascular coupling. Our study explored just 1 component (autoregulation) of this integrated regulatory system, which may be, as Dr Shang suggested, mostly reflective of regulation of blood flow in pial arteries.…”