Integrative Physiological Aspects of Brain RAS in Hypertension

Abstract

Studies using neuronal or glial-specifc mouse models have allowed for greater understanding into the site-specific expression and role centrally expressed RAS proteins have on BP regulation. While all components of the RAS have been identified in cardiovascular regulatory regions of the brain, their actions may be site specific. In a number of animal models of hypertension, reduction in Ang II-mediated signaling, or upregulation of the central ACE2/Ang 1-7 pathway, has been shown to reduce BP, via a reduction in sympathetic signaling and increase parasympathetic tone, respectively. Emerging evidence also suggests that, in part, the female protective phenotype against hypertension may be due to inceased ACE2 activity within cardiovascular regulatory regions of the brain, potentially mediated by estrogen. Increasing evidence suggests the importance of a central renin-angiotensin pathway, although its localization and the mechanisms involved in its expression and regulation still need to be clarified and more precisely defined. All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

Within the Brain: The Renin Angiotensin System

“…More studies evaluating sex differences within the angiotensin system and cognitive impairment are needed. Aging and disease states such as hypertension and diabetes can precipitate a dysregulation of the angiotensin system and can be reviewed here [ 18 , 145 , 146 ]. More studies are needed to evaluate the modulation of the angiotensin system and its contribution to the increased incidence of cognitive impairment observed in aging, hypertension and diabetes.…”

Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders?

“…Indeed, the brain is the organ with the highest MasR expression, and high Ang (1–7) concentrations have been detected in the brain ( Huber et al., 2017 ). ACE2 is expressed in brain endothelium, neurons, and probably in glial cells ( Hamming et al., 2004 ; Gallagher et al., 2006 ; Matsushita et al., 2010 ; Gowrisankar and Clark, 2016 ; Xu et al., 2017 ; de Morais et al., 2018 ). The proposed SARS-CoV-2-induced depletion of ACE2 has the potential to induce severe consequences in brain RAS system by altering the ATR1/MasR balance toward the neuroinflammation.…”

“…The proposed SARS-CoV-2-induced depletion of ACE2 has the potential to induce severe consequences in brain RAS system by altering the ATR1/MasR balance toward the neuroinflammation. For example, ATR1 activation on microglia activates NF-κB and the release of proinflammatory cytokines ( Shi et al., 2014 ; de Morais et al., 2018 ) that may induce subsequent astroglial proinflammatory response ( Figure 3 ). Indeed, reduced activity of the Ang (1–7)/MasR pathway would decrease the antioxidant and anti-inflammatory mediators in the brain parenchyma ( Figure 3 ).…”

Central nervous system neuroplasticity and the sensitization of hypertension

“…It is now recognized that most components of the RAAS are synthesized in the CNS as well as at many sites in the body, including the vascular wall, heart, adipose tissue, haemopoietic bone marrow, lungs, and the gastrointestinal tract 62,63 . Although some controversy remains, work by many contributors has resulted in a general consensus that essentially all RAAS components are generated de novo within the mammalian CNS and that the weight of the evidence favours the existence of a brain RAAS 67–71 .…”