- Poster presentation
- Open Access
cGMP and PKGI are required for vascular BMP signaling
BMC Pharmacology volume 11, Article number: P65 (2011)
Maintenance of vascular homeostasis depends on phenotypic switching of vascular smooth muscle cells (VSMCs) during development, vascular injury repair, and disease. In healthy blood vessels, VSMCs exhibit a differentiated, ‘contractile’ phenotype, but in diseased vascular tissue or after vascular injury, they de-differentiate into a ‘synthetic’ state, characterized by decreased smooth muscle (SM)-specific gene expression and increased proliferation and motility .
Although still controversial, a large number of studies indicate that the NO/cGMP/PKGI pathway inhibits proliferation and de-differentiation of VSMCs. Subcultured primary VSMCs undergo de-differentiation to a ‘synthetic’ phenotype with both reduced SM-specific gene expression and loss of PKGI expression. A more ‘contractile’ phenotype can be regained by restoring PKGI . PKGI stimulates SM-specific gene expression through regulation of the cystein-rich LIM only protein CRP4 that cooperates with SRF-containing transcription complexes . But the mechanism how cGMP/PKGI regulates SM-specific phenotype is incompletely understood. In C2C12 myoblasts, PKGI phosphorylates the BMP type II receptor (BMPRII); in response to BMP-2, PKGI dissociates from the receptor, associates with the activated Smad1/4 complex, translocates to the nucleus, and forms a complex with Smads and the general transcription factor TFII-I to collaboratively activate transcription . In the vascular system, BMP signaling inhibits proliferation and migration of VSMCs, and upregulates SM-specific genes, through Smad-dependent [5–8] and/or Smad-independent pathways [9–11]. Interestingly, heterozygous germline mutations within BMPRII can cause pulmonary arterial hypertension (PAH), a disease characterized by thickening of pulmonary arteries due to abnormal proliferation, migration, and/or apoptosis of VSMCs and endothelial cells . Considering these data we hypothesize that PKGI promotes the differentiated ‘contractile’ phenotype of VSMCs at least in part through enhancing vascular BMP/Smad signaling. Indeed we found that cGMP/PKGI promoted Smad1/5 activation and BMP target gene expression in VSMCs and SM precursor cells. Pharmacological or siRNA-mediated inhibition of the NO/cGMP/PKGI pathway not only suppressed BMP-induced upregulation of SM-specific gene transcription, but also abrogated the anti-proliferative and anti-migratory effects of BMP on VSMCs. Furthermore preliminary data suggest that Smad crosstalk with other transcriptional regulators is involved.
Our data imply that within the vasculature, PKGI is a critical regulator of the VSMC differentiation-promoting effects of BMP. The integration of cGMP/PKGI pathway into BMP/Smad signaling in the vascular system might provide new insight into the mechanisms of vascular remodeling in diseases such as atherosclerosis, vascular restenosis and pulmonary hypertension.
Owens GK, Kumar MS, Wamhoff BR: Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev. 2004, 84: 767-801. 10.1152/physrev.00041.2003.
Lincoln TM, Wu X, Sellak H, Dey N, Choi CS: Regulation of vascular smooth muscle cell phenotype by cyclic GMP and cyclic GMP-dependent protein kinase. Front Biosci. 2006, 11: 356-367. 10.2741/1803.
Zhang T, Zhuang S, Casteel DE, Looney DJ, Boss GR, Pilz RB: A cysteine-rich LIM-only protein mediates regulation of smooth muscle-specific gene expression by cGMP-dependent protein kinase. J Biol Chem. 2007, 282: 33367-33380. 10.1074/jbc.M707186200.
Schwappacher R, Weiske J, Heining E, Ezerski V, Marom B, Henis YI, Huber O, Knaus P: Novel crosstalk to BMP signalling: cGMP-dependent kinase I modulates BMP receptor and Smad activity. EMBO J. 2009, 28: 1537-1550. 10.1038/emboj.2009.103.
Lagna G, Ku MM, Nguyen PH, Neuman NA, Davis BN, Hata A: Control of phenotypic plasticity of smooth muscle cells by bone morphogenetic protein signaling through the myocardin-related transcription factors. J Biol Chem. 2007, 282: 37244-37255. 10.1074/jbc.M708137200.
Chan MC, Hilyard AC, Wu C, Davis BN, Hill NS, Lal A, Lieberman J, Lagna G, Hata A: Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression. Embo J. 2010, 29: 559-573. 10.1038/emboj.2009.370.
Davis BN, Hilyard AC, Lagna G, Hata A: SMAD proteins control DROSHA-mediated microRNA maturation. Nature. 2008, 454: 56-61. 10.1038/nature07086.
Chan MC, Weisman AS, Kang H, Nguyen PH, Hickman T, Mecker SV, Hill NS, Lagna G, Hata A: The amiloride derivative phenamil attenuates pulmonary vascular remodeling by activating NFAT and the bone morphogenetic protein signaling pathway. Mol Cell Biol. 2011, 31: 517-530. 10.1128/MCB.00884-10.
Hansmann G, de Jesus Perez VA, Alastalo TP, Alvira CM, Guignabert C, Bekker JM, Schellong S, Urashima T, Wang L, Morrell NW, Rabinovitch M: An antiproliferative BMP-2/PPARgamma/apoE axis in human and murine SMCs and its role in pulmonary hypertension. J Clin Invest. 2008, 118: 1846-1857. 10.1172/JCI32503.
Yang J, Li X, Al-Lamki RS, Southwood M, Zhao J, Lever AM, Grimminger F, Schermuly RT, Morrell NW: Smad-dependent and smad-independent induction of id1 by prostacyclin analogues inhibits proliferation of pulmonary artery smooth muscle cells in vitro and in vivo. Circ Res. 2010, 107: 252-262. 10.1161/CIRCRESAHA.109.209940.
Perez VA, Ali Z, Alastalo TP, Ikeno F, Sawada H, Lai YJ, Kleisli T, Spiekerkoetter E, Qu X, Rubinos LH, Ashley E, Amieva M, Dedhar S, Rabinovitch M: BMP promotes motility and represses growth of smooth muscle cells by activation of tandem Wnt pathways. J Cell Biol. 2011, 192: 171-188. 10.1083/jcb.201008060.
Morrell NW: Role of bone morphogenetic protein receptors in the development of pulmonary arterial hypertension. Adv Exp Med Biol. 2010, 661: 251-264. 10.1007/978-1-60761-500-2_16.
Rights and permissions
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
About this article
Cite this article
Schwappacher, R., Diep, T., Boss, G. et al. cGMP and PKGI are required for vascular BMP signaling. BMC Pharmacol 11 (Suppl 1), P65 (2011). https://doi.org/10.1186/1471-2210-11-S1-P65
- Pulmonary Hypertension
- Pulmonary Arterial Hypertension
- Vascular Injury
- Specific Gene Expression
- C2C12 Myoblast