OBJECTIVE: Vascular remodeling occurs after endothelial injury, resulting in smooth muscle cell (SMC) proliferation and vascular fibrosis. We previously demonstrated that the blood pressure-regulating hormone aldosterone enhances vascular remodeling in mice at sites of endothelial injury in a placental growth factor-dependent manner. We now test the hypothesis that SMC mineralocorticoid receptors (MRs) directly mediate the remodeling effects of aldosterone and further explore the mechanism. APPROACH AND RESULTS: A wire-induced carotid injury model was performed in wild-type mice and mice with inducible SMC-specific deletion of the MR. Aldosterone did not affect re-endothelialization after injury in wild-type mice. Deletion of SMC-MR prevented the 79% increase in SMC proliferation induced by aldosterone after injury in MR-Intact littermates. Moreover, both injury-induced and aldosterone-enhanced vascular fibrosis were attenuated in SMC-specific MR knockout mice. Further exploration of the mechanism revealed that aldosterone-induced vascular remodeling is prevented by in vivo blockade of the placental growth factor-specific receptor, type 1 vascular endothelial growth factor receptor (VEGFR1), the receptor for placental growth factor. Immunohistochemistry of carotid vessels shows that the induction of VEGFR1 expression in SMC after vascular injury is attenuated by 72% in SMC-specific MR knockout mice. Moreover, aldosterone induction of vascular placental growth factor mRNA expression and protein release are also prevented in vessels lacking SMC-MR. CONCLUSIONS: These studies reveal that SMC-MR is necessary for aldosterone-induced vascular remodeling independent of renal effects on blood pressure. SMC-MR contributes to induction of SMC VEGFR1 in the area of vascular injury and to aldosterone-enhanced vascular placental growth factor expression and hence the detrimental effects of aldosterone are prevented by VEGFR1 blockade. This study supports exploring MR antagonists and VEGFR1 blockade to prevent pathological vascular remodeling induced by aldosterone.
OBJECTIVE: Vascular remodeling occurs after endothelial injury, resulting in smooth muscle cell (SMC) proliferation and vascular fibrosis. We previously demonstrated that the blood pressure-regulating hormone aldosterone enhances vascular remodeling in mice at sites of endothelial injury in a placental growth factor-dependent manner. We now test the hypothesis that SMC mineralocorticoid receptors (MRs) directly mediate the remodeling effects of aldosterone and further explore the mechanism. APPROACH AND RESULTS: A wire-induced carotid injury model was performed in wild-type mice and mice with inducible SMC-specific deletion of the MR. Aldosterone did not affect re-endothelialization after injury in wild-type mice. Deletion of SMC-MR prevented the 79% increase in SMC proliferation induced by aldosterone after injury in MR-Intact littermates. Moreover, both injury-induced and aldosterone-enhanced vascular fibrosis were attenuated in SMC-specific MR knockout mice. Further exploration of the mechanism revealed that aldosterone-induced vascular remodeling is prevented by in vivo blockade of the placental growth factor-specific receptor, type 1 vascular endothelial growth factor receptor (VEGFR1), the receptor for placental growth factor. Immunohistochemistry of carotid vessels shows that the induction of VEGFR1 expression in SMC after vascular injury is attenuated by 72% in SMC-specific MR knockout mice. Moreover, aldosterone induction of vascular placental growth factor mRNA expression and protein release are also prevented in vessels lacking SMC-MR. CONCLUSIONS: These studies reveal that SMC-MR is necessary for aldosterone-induced vascular remodeling independent of renal effects on blood pressure. SMC-MR contributes to induction of SMC VEGFR1 in the area of vascular injury and to aldosterone-enhanced vascular placental growth factor expression and hence the detrimental effects of aldosterone are prevented by VEGFR1 blockade. This study supports exploring MR antagonists and VEGFR1 blockade to prevent pathological vascular remodeling induced by aldosterone.
Authors: Faiez Zannad; John J V McMurray; Henry Krum; Dirk J van Veldhuisen; Karl Swedberg; Harry Shi; John Vincent; Stuart J Pocock; Bertram Pitt Journal: N Engl J Med Date: 2010-11-14 Impact factor: 91.245
Authors: Fabrice Ivanes; Sophie Susen; Frédéric Mouquet; Pascal Pigny; François Cuilleret; Karine Sautière; Jean-Philippe Collet; Farzin Beygui; Bernadette Hennache; Pierre Vladimir Ennezat; Françis Juthier; Florence Richard; Jean Dallongeville; Marieke A Hillaert; Pieter A Doevendans; Brigitte Jude; Michel Bertrand; Gilles Montalescot; Eric Van Belle Journal: Eur Heart J Date: 2011-06-30 Impact factor: 29.983
Authors: David A Calhoun; Daniel Jones; Stephen Textor; David C Goff; Timothy P Murphy; Robert D Toto; Anthony White; William C Cushman; William White; Domenic Sica; Keith Ferdinand; Thomas D Giles; Bonita Falkner; Robert M Carey Journal: Circulation Date: 2008-06-24 Impact factor: 29.690
Authors: Massimiliano Caprio; Brenna G Newfell; Andrea la Sala; Wendy Baur; Andrea Fabbri; Giuseppe Rosano; Michael E Mendelsohn; Iris Z Jaffe Journal: Circ Res Date: 2008-05-08 Impact factor: 17.367
Authors: Amy McCurley; Paulo W Pires; Shawn B Bender; Mark Aronovitz; Michelle J Zhao; Daniel Metzger; Pierre Chambon; Michael A Hill; Anne M Dorrance; Michael E Mendelsohn; Iris Z Jaffe Journal: Nat Med Date: 2012-09 Impact factor: 53.440
Authors: Adam P McGraw; Jessamyn Bagley; Wei-Sheng Chen; Carol Galayda; Heather Nickerson; Andrea Armani; Massimiliano Caprio; Peter Carmeliet; Iris Z Jaffe Journal: J Am Heart Assoc Date: 2013-02-22 Impact factor: 5.501
Authors: Ana Paula Davel; Iris Z Jaffe; Rita C Tostes; Frederic Jaisser; Eric J Belin de Chantemèle Journal: Am J Physiol Heart Circ Physiol Date: 2018-06-29 Impact factor: 4.733
Authors: Qing Lu; Ana P Davel; Adam P McGraw; Sitara P Rao; Brenna G Newfell; Iris Z Jaffe Journal: Endocrinology Date: 2019-09-01 Impact factor: 4.736