Although endoplasmic reticulum (ER) stress is a pathologic mechanism in a variety of chronic diseases, it is unclear what role it plays in chronic hypertension (HTN). Dysregulation of brain mechanisms controlling arterial pressure is strongly implicated in HTN, particularly in models involving angiotensin II (Ang II). We tested the hypothesis that ER stress in the brain is causally linked to Ang II–dependent HTN. Chronic systemic infusion of low-dose Ang II in C57BL/6 mice induced slowly developing HTN, which was abolished by co-infusion of the ER stress inhibitor tauroursodeoxycholic acid (TUDCA) into the lateral cerebroventricle. Investigations of the brain regions involved revealed robust increases in ER stress biomarkers and profound ER morphological abnormalities in the circumventricular subfornical organ (SFO), a region outside the blood-brain barrier and replete with Ang II receptors. Ang II–induced HTN could be prevented in this model by selective genetic supplementation of the ER chaperone 78-kDa glucose-regulated protein (GRP78) in the SFO. These data demonstrate that Ang II–dependent HTN is mediated by ER stress in the brain, particularly the SFO. To our knowledge, this is the first report that ER stress, notably brain ER stress, plays a key role in chronic HTN. Taken together, these findings may have broad implications for the pathophysiology of this disease.
Colin N. Young, Xian Cao, Mallikarjuna R. Guruju, Joseph P. Pierce, Donald A. Morgan, Gang Wang, Costantino Iadecola, Allyn L. Mark, Robin L. Davisson
Submitter: Matrougui Matrougui | firstname.lastname@example.org
Authors: Mohamed Trebak, Modar Kassan
Eastern Virginia Medical School
Published December 27, 2012
Kassan & Matrougui: Department of Physiological Sciences, Eastern Virginia School of Medicine, 700 W Olney Rd, Norfolk, Virginia 23501; Trebal M: College of Nanoscale Science and Engineering University at Albany 257 Fuller Rd. Albany, NY 12203
We read with great interest the recent article by Young et al (1) reporting that endoplasmic reticulum stress induction, in circumventricular subfornical organ (SFO), as key element in the increase of blood pressure in mice infused with angiotensin II. We would like to highlight important information that links the present study to our previous published work and provide explanations on the regulation of blood pressure and vascular function.
We previously reported that C57BL/6 mice infused with angiotensin II displayed an increase in blood pressure, cardiac hypertrophy and endoplasmic reticulum (ER) stress markers in heart and vasculature, which were blunted after ER stress inhibition (2). We also showed that ER stress inhibition improves vascular endothelium-dependent relaxation in arteries of mice infused with Ang II. The study by Young et al (1) answers the important question of how local inhibition of ER stress in SFO of mice infused with Ang II reduces blood pressure and therefore improves peripheral vascular function? The structure of the SFO is characterized by an extensive vasculature and lack of normal blood brain barrier and it is likely that the local injection of Tudca in the SFO region could leak into the systemic circulation and inhibit ER stress induction in the whole cardiovascular system, which would result in blood pressure reduction as we previously reported (2). The effect of ER stress inhibition on vascular function is independent of blood pressure since we demonstrated that tunicamycin (an ER stress inducer) did not increase blood pressure but impaired vascular endothelium-dependent relaxation. These effects were blunted with Tudca indicating that induction of ER stress impairs vascular function independently of blood pressure changes (2). The ER stress in SFO linked to blood pressure regulation observed by Young et al (1) is quite intriguing. It has been shown that the immune system is involved in the regulation of blood pressure and vascular function in in a mouse model of hypertension where C57BL/6 mice were infused with Ang II (3). In this model, we reported that immune regulatory T cell number is reduced in an apoptosis-dependent mechanism, which leads to increases in blood pressure and impaired vascular function (3). It is possible that in the model of hypertension induced by Ang II, there is induction of ER stress in immune regulatory T cells. The leak of Tudca from the SFO could therefore inhibit ER stress in these immune regulatory T cells, which would result in blood pressure reduction and improvement of vascular function. The study by Young et al (1) provides important insights into the role of SFO ER stress in blood pressure regulation. However, future studies are needed to determine the precise mechanisms involved and determine the involvement of ER stress in SFO versus ER stress in the systemic vasculature in hypertension.