Serotonin and the Rho Signaling Pathway in Smooth Muscle Cells

Summary

Principal Investigator: BARRY FANBURG
Abstract: DESCRIPTION (provided by applicant): Clinical, animal experimental and human genetic information currently support a relationship of serotonin ( 5- HT) to pulmonary hypertension (PH). Studies by us and others have indicated the importance of both the 5- HT transporter (5-HTT) and 5-HT receptors (5-HTRs) in the pulmonary vascular smooth muscle cell (SMC) proliferative response to 5-HT. We have identified collaborative actions of the 5-HTT and 5-HTRs through independent stimulations of signaling pathways in the proliferative response. MARK is activated through the 5-HTT and activation of the Rho pathway via 5-HT 1B participates in translocation of MARK from SMC cytoplasm to nucleus. More recently, we have also found that 5-HT transactivates the PDGF receptor (R) and interference of this activation by Gleevec, a tyrosine kinase inhibitor, blocks 5-HT-induced SMC proliferation. The Rho pathway plays a central role in 5-HT-induced SMC proliferation and has been reported to participate in hypoxia-induced PH;importantly, agents are currently available to modify this pathway. We hypothesize that activation of the Rho pathway and transactivation of PDGFR participate in SMC proliferative and migratory processes important in development of PH. We wish in this proposal to better study the 5-HT-related signaling pathways in vitro and in vivo that orchestrate SMC proliferation and migration. To do this we plan to: 1) Further define upstream and downstream effectors of 5-HT-induced Rho signaling in SMCs in culture that lead to SMC proliferation and migration;2) Determine the effect and mechanisms of action of statins and other geranylgeranyl and farnesyl transferase inhibitors on the 5-HT- induced SMC responses;3) Evaluate the role of transactivation of PDGFR by 5-HT in SMC proliferative and migratory responses;and 4) Correlate the signaling pathways occurring in vitro with those operative in vivo with the use of wild type and 5-HTT and 5-HTR transgenic mice exposed to hypoxia and infused with 5-HT by osmotic pumps. We believe the overall experiments will provide a better appreciation of 5-HT-related cell signaling pathways that may be operative in PH and may allow new approaches to therapy of this disease.
Funding Period: ----------------2007 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells
    Lin Wei
    Tufts Medical Center and Tupper Research Institute, Boston, Massachusetts 02111, USA
    Am J Physiol Lung Cell Mol Physiol 298:L863-9. 2010
  2. pmc Role of protein transamidation in serotonin-induced proliferation and migration of pulmonary artery smooth muscle cells
    Yinglin Liu
    Rutgers University, Piscataway, New Jersey, USA
    Am J Respir Cell Mol Biol 44:548-55. 2011
  3. pmc The Lbc Rho guanine nucleotide exchange factor α-catulin axis functions in serotonin-induced vascular smooth muscle cell mitogenesis and RhoA/ROCK activation
    Michael D Bear
    Division of Pulmonary and Critical Care, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
    J Biol Chem 285:32919-26. 2010
  4. pmc Serotonin transporter interacts with the PDGFβ receptor in PDGF-BB-induced signaling and mitogenesis in pulmonary artery smooth muscle cells
    Wenying Ren
    Department of Medicine, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
    Am J Physiol Lung Cell Mol Physiol 300:L486-97. 2011
  5. pmc Serotonylated fibronectin is elevated in pulmonary hypertension
    Lin Wei
    Tufts University School of Medicine, Tufts Medical Center, Tupper Research Institute, Boston, MA 02111, USA
    Am J Physiol Lung Cell Mol Physiol 302:L1273-9. 2012

Detail Information

Publications5

  1. pmc JNK regulates serotonin-mediated proliferation and migration of pulmonary artery smooth muscle cells
    Lin Wei
    Tufts Medical Center and Tupper Research Institute, Boston, Massachusetts 02111, USA
    Am J Physiol Lung Cell Mol Physiol 298:L863-9. 2010
    ..Its activation by 5-HT is initiated through 5-HT (1B) and (2A) receptors, and its stimulation of SMC proliferation and migration occurs through the Akt pathway...
  2. pmc Role of protein transamidation in serotonin-induced proliferation and migration of pulmonary artery smooth muscle cells
    Yinglin Liu
    Rutgers University, Piscataway, New Jersey, USA
    Am J Respir Cell Mol Biol 44:548-55. 2011
    ....
  3. pmc The Lbc Rho guanine nucleotide exchange factor α-catulin axis functions in serotonin-induced vascular smooth muscle cell mitogenesis and RhoA/ROCK activation
    Michael D Bear
    Division of Pulmonary and Critical Care, Tupper Research Institute, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111, USA
    J Biol Chem 285:32919-26. 2010
    ..Thus, the Lbc/α-catulin axis participates in 5-HT-induced PASMC mitogenesis and RhoA/ROCK signaling, and may be an interventional target in diseases involving vascular smooth muscle remodeling...
  4. pmc Serotonin transporter interacts with the PDGFβ receptor in PDGF-BB-induced signaling and mitogenesis in pulmonary artery smooth muscle cells
    Wenying Ren
    Department of Medicine, Tupper Research Institute, Tufts Medical Center, Boston, Massachusetts, USA
    Am J Physiol Lung Cell Mol Physiol 300:L486-97. 2011
    ..In total, the data show for the first time an important interactive relationship between SERT and the PDGFRβ in the production of PASMC proliferation triggered by PDGF that may be important in PH...
  5. pmc Serotonylated fibronectin is elevated in pulmonary hypertension
    Lin Wei
    Tufts University School of Medicine, Tufts Medical Center, Tupper Research Institute, Boston, MA 02111, USA
    Am J Physiol Lung Cell Mol Physiol 302:L1273-9. 2012
    ..77). TGase-bound FN also was increased in experimental PH. We conclude that increased serotonylation of FN occurs in human and experimental PH and may provide a biomarker for the disease...