Therapeutic potential of the epidermal growth factor receptor transactivation in hypertension: a convergent signaling pathway of vascular tone, oxidative stress, and hypertrophic growth downstream of vasoactive G-protein-coupled receptors?
The concurrence of enhanced vascular tone, oxidative stress, and hypertrophic growth is a hallmark of hypertension, the condition characterized by sustained elevated blood pressure. However, it is unclear how and why such apparently distinct processes coincide in hypertension. Elevated levels of certain vasoactive G-protein-coupled receptor agonists (such as catecholamines, endothelin-1, and angiotensin II) can explain, at least in part, the development and progression of many hypertensive disorders. Here, we review findings made by other investigators and ourselves suggesting that enhanced vascular tone, oxidative stress, and hypertrophic growth characteristically induced by these agonists involve the transactivation of growth factor receptors. The first step in this transactivation mechanism is agonist-induced activation of metalloproteinase-dependent shedding of growth factors. Shed growth factors then trigger intracellular signaling cascades necessary for growth, production of reactive oxygen species, and maintenance of vascular tone. If this hypothesis is proven generally correct, then transactivation blockers have general therapeutic potential in hypertension regardless of the causative agonist.
Fernandez-Patron
Carlos
C
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada. cf2@ualberta.ca
D051722:ADAM Proteins / Q000378:metabolism; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D045726:Metalloproteases / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000378:metabolism
D000959:Antihypertensive Agents; D017382:Reactive Oxygen Species; D018340:Receptors, Adrenergic, alpha-1; D043562:Receptors, G-Protein-Coupled; D014662:Vasoconstrictor Agents; D066246:ErbB Receptors; D045726:Metalloproteases; D051722:ADAM Proteins