Angiogenesis, or new blood vessel formation from existing vessels, is critical to normal development and wound healing, cancer metastases, diabetic proliferative retinopathy and hemangioma formation. Endothelial cell invasion of matrix, proliferation, and migration to sites of new vessel branching from existing vessels is regulated by factors, such as vascular endothelial cell growth factor (VEGF). We have recently found that the vasoactive proteins, the endothelins, stimulate VEGF transcription, synthesis, and secretion from cultured human vascular smooth muscle cells (VSMC). Further, we identified the natriuretic peptide (NP) family of vascular proteins as the first endogenous inhibitors of VEGF synthesis, and VEGF action. We propose to determine the proximal mechanisms by which these vasoactive peptides modulate VEGF synthesis in cultured human VSMC. We believe that endothelin-1 (ET-1) triggers activation of Gq and Gi proteins leading to intracellular signal transduction culminating in ERK activation and VEGF transcription. NP inhibits this mainly through the clearance receptor, and a novel mechanism via the activation of RGS proteins or inhibition of G protein palmitoylation. We will measure each of these events and show modulation in response to ET, and by NP. The importance of G protein dynamics for NP-inhibition of ET-stimulated MAP-kinase (Erk) activity and VEGF transcription will be shown, linking these events. It is also possible that NP activate a MAP kinase related phosphatase, and we will determine if NP stimulate the synthesis and activity of MKP-1 and MKP-2, inhibited by ET-1. This would implicate this mechanism for the inactivation of ERK- signaling to VEGF transcription. We will then determine the signaling mechanisms by which VEGF stimulates EC proliferation, and the inhibition of this mechanism by ANP. This involves signaling through a novel ERK to JNK cross-activation cascade, which is inhibited by the NP, modulating specific cell cycle events such as cyclin D1 production and Cdk4 activation which are critical to G1/S progression in these cells. These will be shown by protein synthesis and kinase activity studies, in cells transfected with dominant negative SEK-1 (JNK kinase) and JNK-1, or PD98059 (Mek inhibitor).

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Goldman, Stephen
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University of California Irvine
Internal Medicine/Medicine
Schools of Medicine
United States
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Guo, Xiaomei; Razandi, Mahnaz; Pedram, Ali et al. (2005) Estrogen induces vascular wall dilation: mediation through kinase signaling to nitric oxide and estrogen receptors alpha and beta. J Biol Chem 280:19704-10
Razandi, Mahnaz; Pedram, Ali; Merchenthaler, Istvan et al. (2004) Plasma membrane estrogen receptors exist and functions as dimers. Mol Endocrinol 18:2854-65
Razandi, Mahnaz; Pedram, Ali; Rosen, Eliot M et al. (2004) BRCA1 inhibits membrane estrogen and growth factor receptor signaling to cell proliferation in breast cancer. Mol Cell Biol 24:5900-13
Razandi, Mahnaz; Alton, Gordon; Pedram, Ali et al. (2003) Identification of a structural determinant necessary for the localization and function of estrogen receptor alpha at the plasma membrane. Mol Cell Biol 23:1633-46
Levin, Ellis R (2003) Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol 17:309-17
Razandi, Mahnaz; Pedram, Ali; Park, Steven T et al. (2003) Proximal events in signaling by plasma membrane estrogen receptors. J Biol Chem 278:2701-12
Pedram, Ali; Razandi, Mahnaz; Levin, Ellis R (2002) Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. J Biol Chem 277:44385-98
Razandi, Mahnaz; Oh, Philip; Pedram, Ali et al. (2002) ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol Endocrinol 16:100-15
Pedram, Ali; Razandi, Mahnaz; Aitkenhead, Mark et al. (2002) Integration of the non-genomic and genomic actions of estrogen. Membrane-initiated signaling by steroid to transcription and cell biology. J Biol Chem 277:50768-75
Levin, Ellis R (2002) Cellular functions of plasma membrane estrogen receptors. Steroids 67:471-5

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