Editors' ChoiceHypertension

The Brain Rules

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Science Translational Medicine  21 Nov 2012:
Vol. 4, Issue 161, pp. 161ec210
DOI: 10.1126/scitranslmed.3005326

Called the “silent killer,” high blood pressure—hypertension—occurs in one-third of adults in the United States alone, and many are unaware of their condition. Chronic elevation in blood pressure in the arteries is an established risk factor for heart attack and stroke, but for most cases of hypertension, the cause is unknown. Now, Young et al. demonstrate a new biological pathway for an old molecule known to play a role in hypertension.

About 5 to 10% of the time, high blood pressure is caused by another condition or disease and therefore, in principle, treatable with a curative approach. However, most people need blood pressure–lowering drugs, such as inhibitors of angiotensin-converting enzyme to limit associated heart and vascular diseases. This class of drugs effectively limits the action of angiotensin II on renal sodium reabsorption, adrenal aldosterone release, and direct vasoconstriction, all of which promote high blood pressure.

In an animal model, Young et al. found that circulating angiotensin II also acts on brain structures in the periventricular region by inducing endoplasmic reticulum (ER) stress; this results in activation of the sympathetic nervous system and subsequent elevation of systemic arterial pressure. The ER effect by angiotensin II is restricted to cerebral structures not shielded by the blood brain barrier—for example, the circumventricular subfornical organ (SFO). Short-term injection of thapsigargin—a chemical that evokes generalized ER stress—in the lateral brain ventricle or long-term systemic application of angiotensin II both induced ER stress within the SFO. This response was revealed by an increase in expression of stress protein–encoding mRNAs and ultrastructural changes in the ER detected by electron microscopy analysis. Arterial hypertension mediated by angiotensin II–induced ER stress was inhibited by SFO-targeted microinjection of an adenoviral vector that expressed GRP78, an ER chaperone known to abrogate ER stress in vivo. The authors also confirmed that angiotensin II induces oxidative stress within the SFO that precedes the ER stress response.

The observation that angiotensin II promotes ER stress within a specialized part of the brain might point to new targets and treatment options for the silent killer. However, chronic stress responses have been linked with diseases such as diabetes mellitus, and acute ER stress responses facilitate adaptation to acute cellular perturbations. Thus, more work is needed to assess whether the new findings translate to human patients and whether ER stress can be quelled in the SFO without causing adverse side effects.

C. N. Young et al., ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension. J. Clin. Invest. 122, 3960–3964 (2012). [Abstract]

Footnotes

  • Is the hyphen correct here? Something seems to be missing.

  • Revised to avoid two contrast words so closely together.

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