Mineralocorticoid and Epidermal Growth Factor Receptors Editorial Commentary Mineralocorticoid and Epidermal Growth Factor Receptors Partners In Vivo Amanda J. Rickard, Peter J. Fuller See related article, pp 238 –244 In the decade since the publication of the RandomizedAldactone Evaluation Study (RALES),1 interest in the role of aldosterone and the mineralocorticoid receptor (MR) has increased exponentially. The comfortable notion that miner- alocorticoid hypertension was just a matter of salt and water has been supplanted by a recognition that multiple tissues and systems are impacted.2,3 It is clear that the adverse cardiovascular consequences of mineralocorticoid-induced hypertension are far in excess of what might be expected for the magnitude and duration of the blood pressure rise.4 These observations have focused re- search on the consequences of MR activation in nonepithelial tissues.5 This represents somewhat of a renaissance as the consequences for the cardiovascular system of exposure to mineralocorticoids was first noted by Hans Seyle in 1946 and rediscovered by Brilla and Weber with further characteriza- tion by Young et al.6 These investigators established a robust rodent model of mineralocorticoid-induced hypertension, car- diac hypertrophy, and cardiac fibrosis resulting from miner- alocorticoid/salt administration over a period of weeks. The cardiac fibrosis is preceded by vascular inflammation and is independent of the hypertension, cardiac hypertrophy, angio- tensin II, and potassium status. It is blocked by coadminis- tration of MR antagonists (spironolactone or eplerenone) and, more importantly, once established, as in RALES, can be reversed by MR blockade.6 The response involves a number of tissues and/or cell types, including vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, and inflammatory cells, particularly those of the monocyte/macrophage lineage. The identification of the relative contribution of each of these cell types, all of which, with the exception of the fibroblasts, contain the MR, is a critical first step in understanding the response. In Hypertension last year, tissue-specific deletion of MR was used to demonstrate a critical role for macrophage MR in the pathological response, although curiously this was without effect on the mononuclear cell infiltration per se.7 Several lines of available evidence clearly demonstrate an important role also for endothelial cells in the response to aldosterone.8 In this issue of the journal, Griol-Charhbili et al9 describe their studies using an established mutant mouse to explore the role of the epidermal growth factor receptor (EGFR) in the vascular response to MR activation. Why the EGFR? Grossmann and Gekle10 have shown that aldosterone can induce rapid (5- to 10-minute) activation of extracellular signal-regulated kinase signaling through the EGFR. This response appears to involve MR, but not in a classic genomic pathway; the activation involves the cytoso- lic tyrosine kinase cSrc, which is known to activate EGFR.10 Activation of the EGFR and its downstream effectors, such as extracellular signal-regulated kinase, is proliferative, and, indeed, the effects of angiotensin on extracellular signal- regulated kinase activity also involve the EGFR. Griol- Charhbili et al9 seek to directly address the role of the EGFR in mediating mineralocorticoid/salt-induced vascular damage in vivo. The approach used is elegant in its simplicity. They take an “off-the-shelf” EGFR knockout mouse, the waved-2 mouse from the Jackson Laboratories, and explore the re- sponse of the vasculature to treatment with aldosterone/salt for 4 weeks. The study focused extensively on the vasculature responses and, thus the consequences for inflammatory cell infiltration, cardiac fibrosis, and so forth, remain to be presented and/or explored. What was found, however, was unexpected. The lack of EGFR signaling did not alter vascular remodeling assessed by morphological criteria, elas- tin, and collagen densities. Lack of EGFR did, however, have consequences for vascular reactivity as measured by aortic relaxation in response to acetylcholine. This appears to be because of diminished levels of endothelial NO synthase in the vessel wall. It should be noted that, at baseline, markers of oxidative stress were increased in the vessel wall of the waved-2 mice, but this did not translate into an altered structural response. One confounder may be that many studies, particularly those examining the coronary vascula- ture, use a longer period of mineralocorticoid/salt treatment, that is, 8 weeks.6,7 Although these results may be interpreted as evidence that the in vitro studies10 have not recapitulated the in vivo situation, there are the usual caveats. In any germline knock- out mouse, the possibility that there is redundancy and/or compensatory mechanisms (which may be recruited during development) must be considered. There are also temporal and spatial considerations. Many of the in vitro studies define responses over minutes rather than weeks. Griol-Charhbili et al9 conclude that the role of the EGFR may be restricted to mediating the acute effects of MR activation, particularly those that occur through rapid nongenomic signaling, a proposition that is certainly consistent with existing data The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia. Correspondence to Peter J. Fuller, Prince Henry’s Institute of Medical Research, PO Box 5152, Clayton Victoria 3168, Australia. E-mail peter.fuller@princehenrys.org (Hypertension. 2011;57:144-145.) © 2011 American Heart Association, Inc. Hypertension is available at http://hyper.ahajournals.org DOI: 10.1161/HYPERTENSIONAHA.110.160895 144 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 (Figure). The relative contribution to the vascular response of the EGFR in the endothelium versus the EFGR in smooth muscle also remains to be determined.9 The question of “why the EGFR?” still hangs; it is only partially resolved. Although the roles of epidermal growth factor clearly extend beyond the dermis, the notion that EGFR serves only as an intermediate in a signaling cascade or in the integration of MR and angiotensin signaling in the vasculature seems improbable. What then is the ligand for the vascular EGFR? Where does it come from? Is it mediating growth or, perhaps, as in the epithelium of the gastrointestinal tract, repair? Yet, growth and/or repair would appear some- what distant from issues of reactivity. Perhaps these questions are captive of the name? In biology, much of the nomencla- ture has a history akin to Christopher Columbus naming the islands of the “New World,” the West Indies. As with all good studies, the work of Griol-Charhbili et al9 raises as many questions as it answers. What is indisputable is that the MR, which also arguably is misnamed, being rather more than just salt and water, plays a diverse role in cardiovascular physiology and pathophysiology. Disclosures None. References 1. Pitt B. Effect of aldosterone blockade in patients with systolic left ven- tricular dysfunction: implications of the RALES and EPHESUS studies. Mol Cell Endocrinol. 2004;217:53–58. 2. Fuller PJ, Young MJ. Mechanisms of mineralocorticoid action. Hypertension. 2005;46:1227–1235. 3. Fujita T. Mineralocorticoid receptors, salt-sensitive hypertension, and metabolic syndrome. Hypertension. 2010;55:813– 818. 4. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005;45:1243–1248. 5. Funder JW. Reconsidering the roles of the mineralocorticoid receptor. Hypertension. 2009;53:286 –290. 6. Young MJ, Lam EY, Richard AJ. Mineralocorticoid receptor activation and cardiac fibrosis. Clin Sci. 2007;112:467– 475. 7. Rickard AJ, Morgan J, Tesch G, Funder JW, Fuller PJ, Young MJ. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension. 2009;54:537–543. 8. Caprio M, Newfell BG, la Sala A, Baur W, Fabbri A, Rosano G, Mendelsohn ME, Jaffe IZ. Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule-1 expression and promote leukocyte adhesion. Circ Res. 2008; 102:1359 –1367. 9. Griol-Charhbili V, Fassot C, Messaoudi S, Perret C, Agrapart V, Jaisser F. Epidermal growth factor receptor mediates the vascular dysfunction but not the remodeling induced by aldosterone/salt. Hypertension. 2011; 57:238 –244. 10. Grossmann C, Gekle M. Non-classical actions of the mineralocorticoid receptor: misues of EGF receptors? Mol Cell Endocrinol. 2007;277:6 –12. Aldosterone MR MR B C A MR MR MR MR Transcription No Transcription E G F R E G F R EGF c-src Ras Raf MEK ERK Figure. Schema demonstrating putative mechanisms involved in MR activation and signaling. A, The classic genomic pathway whereby aldosterone-bound MRs homodimerize and rapidly translocate to the nucleus where they bind specific hor- mone response elements (HRE) to initiate gene transcription. B, Transrepression by aldosterone-bound MR complexes, which interact with other transcription factors in an HRE-independent manner. C, Cytoplas- mic second messenger signaling as a result of ligand-bound MR inducing rapid, non- genomic effects through activation of receptors, such as the EGFR. Rickard and Fuller Mineralocorticoid and EGFRs 145 D ow nloaded from http://ahajournals.org by on A pril 5, 2021