Evidence that remodeling of insular cortex neurovascular unit contributes to hypertension‐related sympathoexcitation

Abstract

The intermediate region of the posterior insular cortex (intermediate IC) mediates sympathoexcitatory responses to the heart and kidneys. Previous studies support hypertension‐evoked changes to the structure and function of neurons, blood vessels, astrocytes and microglia, disrupting the organization of the neurovascular unit (NVU). In this study, we evaluated the functional and anatomical integrity of the NVU at the intermediate IC in the spontaneously hypertensive rat (SHR) and its control the Wistar‐Kyoto (WKY). Under urethane anesthesia, NMDA microinjection (0.2 mmol/L/100 nL) was performed at the intermediate IC with simultaneous recording of renal sympathetic nerve activity (RSNA), heart rate (HR) and mean arterial pressure (MAP). Alterations in NVU structure were investigated by immunofluorescence for NMDA receptors (NR1), blood vessels (70 kDa FITC‐dextran), astrocytes (GFAP), and microglia (Iba1). Injections of NMDA into intermediate IC of SHR evoked higher amplitude responses of RSNA, MAP, and HR. On the other hand, NMDA receptor blockade decreased baseline RSNA, MAP and HR in SHR, with no changes in WKY. Immunofluorescence data from SHR intermediate IC showed increased NMDA receptor density, contributing to the SHR enhanced sympathetic responses, and increased in vascular density (increased number of branches and endpoints, reduced average branch length), suggesting angiogenesis. Additionally, IC from SHR presented increased GFAP immunoreactivity and contact between astrocyte processes and blood vessels. In SHR, IC microglia skeleton analysis supports their activation (reduced number of branches, junctions, endpoints and process length), suggesting an inflammatory process in this region. These findings indicate that neurogenic hypertension in SHR is accompanied by marked alterations to the NVU within the IC and enhanced NMDA‐mediated sympathoexcitatory responses likely contributors of the maintenance of hypertension.

How the insula speaks to the heart: Cardiac responses to insular stimulation in humans

“…In addition, our work reinforces some studies showing functional and structural alterations of the insula in cardiovascular diseases such as hypertension (Marins, Iddings, Fontes, & Filosa, ) or heart failure (Song, Roy, Fonarow, Woo, & Kumar, ). These insula alterations would maintain sympathetic hyperactivity and parasympathetic dysfunction, while it is well documented that these autonomic alterations predict morbidity and mortality in these populations (Malliani et al, ).…”

“…These insula alterations would maintain sympathetic hyperactivity and parasympathetic dysfunction, while it is well documented that these autonomic alterations predict morbidity and mortality in these populations (Malliani et al, ). In particular, a neurovascular remodeling of the insular cortex was revealed in hypertension, which may contribute to the maintenance of sympathetic hyperactivity and of hypertension (Marins et al, ). In heart failure, Song et al () reported functional and structural alterations in the insula correlated with autonomic dysfunctions.…”

The role of the blood–brain barrier in hypertension

“…Interestingly, astrocytes also release vascular endothelial growth factors, which have been shown to disrupt the BBB and increase leucocyte extravasation (Argaw et al 2012). In the spontaneously hypertensive rat, anatomical changes to the intermediate insular cortex, a cardiovascular system-related region, was recently demonstrated (Marins et al 2017). Increased density of the NMDA receptor, angiogenesis, glial fibrillary acidic protein immunoreactivity and microglial activation were found to increase within this region, further supporting the theory that the neurovascular unit appears has a role in autonomic signalling in hypertension.…”

Increased Catecholamine Levels and Inflammatory Mediators Alter Barrier Properties of Brain Microvascular Endothelial Cells in vitro

“…The cardiovascular system is regulated by a central autonomic network consisting among others of the insular cortex, which is exposed to higher risk of cerebrovascular disease (10,33). Damage in insular cortex has been associated with myocardial injury and TTS (10,34).…”