Caveolin-Dependent Angiotensin II Type 1 Receptor Signaling in Vascular Smooth Muscle

Abstract

A ngiotensin II (Ang II) is a pluripotent hormone in vascular smooth muscle cells (VSMCs) and stimulates arterial hypertrophy, a hallmark of remodeling in hypertension. These effects are mediated primarily through the G protein-coupled receptor Ang II type 1 receptor (AT 1 R). 1 In VSMCs, AT 1 R-mediated signaling is biphasic, and internalization of the agonist/receptor complex into what we called a "signaling domain" is required for the tonic phase of signaling (initially characterized by phospholipase D activation) but not for the initial phospholipase C stimulation, which occurs at the cell surface. 2 This evidence was consistent with the existence of spatially discrete Ang II signaling domains. We showed that sequential Ang II-induced phospholipase activation is mediated through Ն2 G␣ subunits (G␣ q and G␣ 12/13 ), as well as their associated G␤␥ components. 3,4 In addition, various nonreceptor tyrosine kinases, including cAbl and some from the Src family, as well as mitogen-activated protein kinases and Akt, are activated by Ang II and mediate VSMC hypertrophy and growth. 5-7 Activation of these pathways is in part dependent on tyrosine phosphorylation (transmodulation) of the epidermal growth factor receptor (EGF-R), which serves as a "scaffold" for the assembly of cSrc and Pyk2, leading to downstream activation of extracellular-regulated kinase (ERK)1/2 and Akt. 8,9 These results are consistent with a model that requires temporal dispersion and organization of the AT 1 R signaling repertoire in VSMCs. 7,10 Accumulating evidence suggests that receptors and the signaling molecules with which they associate are not randomly distributed in the cell membrane but are localized in specialized signaling domains. Functionally distinct microdomains, formed by the lateral packing of glycosphingolipids and cholesterol within the membrane bilayer, have been identified in plasma membranes. These domains, called "lipid rafts," have been implicated in membrane trafficking and cellular signaling mechanisms and serve as "scaffolds" to facilitate the association of signaling complexes, thereby increasing the rate of interactions of receptors, coupling and adaptor molecules, and signaling proteins. 11 Caveolae are cell membrane invaginations that contain the major structural protein caveolin-1 (Cav1) and are thought to be subsets of rafts. They are postulated to be platforms for the coordination of certain signaling pathways. In VSMCs, Ang II stimulation promotes AT 1 R association with Cav1 and trafficking of the receptor from heavy density membrane fractions into relatively buoyant Cav1-enriched lipid rafts, which is required for transactivation of EGF-R at focal adhesions, another membrane signaling domains associated with growth factor and integrin signaling. 7,10,12,13 The full expression of the AT 1 R signaling repertoire depends on caveolae/lipid rafts and reactive oxygen species (ROS) production by reduced nicotinamideadenine dinucleotide phosphate (NADPH) oxidase. 7,10,13,14 Several recent reviews have described the...

Dietary sodium intake regulates angiotensin II type 1, mineralocorticoid receptor, and associated signaling proteins in heart

“…As occurs with ERa, we found an association between both CAV-1 and CAV-3 and the MR. Furthermore, we demonstrated interactions between CAV-3 and AT 1 R, as has been reported (Ushio-Fukai & Alexander 2006), and between MR and AT 1 R. Both AT 1 R and MR were located in the membrane and cytoplasmic fractions, and immunoprecipitation studies revealed strong interactions between MR and AT 1 R in both fractions. These results suggest that the change in co-precipitation of AT 1 R and MR when sodium intake was restricted is likely to be occurring in both fractions.…”

Effect of dietary sodium on vasoconstriction and eNOS-mediated vascular relaxation in caveolin-1-deficient mice

“…In VSM, Cav-1 plays a role in the coupling of ␣-adrenergic, ANG II, and endothelin receptors to VSM contraction and growth (34,38,39,43). In the endothelium, Cav-1 anchors eNOS to caveolae, thus preventing its activation and reducing NO production and vascular relaxation (3,7,33).…”

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Thus, the EGFR, relevant GPCRs (AT1, endothelin, β-adrenergic, muscarinic, opioid, adenosine), G proteins (α and βγ), Src family kinases, and ADAM17 have been reported to be, at least in part, localised to caveolae in non-cardiac cells (Smart et al, 1995;Mineo et al, 1996;Ushio-Fukai and Alexander, 2006;Takaguri et al, 2011).…”