Vascular smooth muscle migration and proliferation in response to lysophosphatidic acid (LPA) is mediated by LPA receptors coupling to Gq

• Published in: Cellular signalling 2006-10, Vol.18 (10), p.1695-1701
• Main Authors: Kim, Jihee, Keys, Janelle R., Eckhart, Andrea D.
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenovirus; Animals; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; DNA - biosynthesis; Enzyme Activation - drug effects; Extracellular Signal-Regulated MAP Kinases - metabolism; G protein coupled receptor; Gene Expression Regulation - drug effects; GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism; Lysophosphatidic acid; Lysophospholipids - pharmacology; Mice; Mice, Transgenic; Microfilament Proteins - metabolism; Migration; Mitogen; Muscle Proteins - metabolism; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Proliferation; Rats; Receptors, Lysophosphatidic Acid - genetics; Receptors, Lysophosphatidic Acid - metabolism; Restenosis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Vascular smooth muscle
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2006.01.009

Many G protein-coupled receptors can couple to multiple G proteins to convey their intracellular signaling cascades. The receptors for lysophosphatidic acid (LPA) possess this ability. LPA receptors are important mediators of a wide variety of biological actions including cell migration, proliferation and survival which are processes that can all have a considerable impact on vascular smooth muscle (VSM) and blood vessels. To date, confirmation of G proteins involved has mostly relied on the inhibition of Gi-mediated signaling via pertussis toxin (PTx). We were interested in the specific involvement of LPA-Gq-mediated signaling therefore we isolated aorta VSM cells (VSMCs) from transgenic mice that express a peptide inhibitor of Gq, GqI, exclusively in VSM. We detected both LPA1 and LPA2 receptor expression in mouse VSM whereas LPA1 and LPA3 were expressed in rat VSM. SM22-GqI did not alter LPA-induced migration but it was sufficient to attenuate LPA-induced proliferation. GqI expression also attenuated LPA-induced ERK1/2 and Akt activation by 40–50%. To test the feasibility of this peptide as a potential therapeutic agent, we also generated adenovirus encoding the GqI. Transient expression of GqI was capable of inhibiting both LPA-induced migration and proliferation of VSMCs isolated from rat and mouse. Furthermore, ERK activation in response to LPA was also attenuated in VSMCs with Adv-GqI. Therefore, LPA receptors couple to Gq in VSMC and mediate migration and proliferation which may be mediated through activation of ERK1/2 and Akt. Our data also suggest that both chronic and transient expression of the GqI peptide is an effective strategy to lower Gq-mediated LPA signaling and may be a successful therapeutic strategy to combat diseases with enhanced VSM growth such as occurs following angioplasty or stent implantation.