Scientist Development Grant: Manikandan Panchatcharam Regulation of Vascular Cells and the Arterial Response to Injury by Lipid Phosphate Phosphatase 3

Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is found in abundance in atherosclerotic plaques and whose production is accelerated by activated platelets. In isolated or cultured systems, LPA stimulates a wide variety of vascular cell responses, including phenotypic modulation of vascular smooth muscle cells (VSMCs), by acting at least in part through a family of G-protein coupled receptors. Thus, LPA is positioned to play a pivotal role in the development of atherosclerosis and restenosis following arterial injury, and using LPA receptor deficient mice, I have recently established the first pathophysiologic role for endogenous LPA in the vasculature. The actions of local and circulating LPA may be terminated by enzymatic dephosphorylation of the lipid by a family of hexahelical membrane spanning proteins, termed lipid phosphate phosphatases (LPP). Of the three LPP enzymes with preference for LPA, LPP3 appears the most likely to play a biologic role in regulating LPA levels, and deficiency of LPP3 results in embyronic lethality in mice due to vascular and neural tube defects. The objective of this proposal is to define the molecular events that are initiated by LPP3 in vascular cells and to assess their contribution to the vascular injury response. Based on my preliminary data, my central hypothesis is that LPP3 terminates Rho-dependent migration and dedifferentiation of VSMCs triggered by exposure to LPA. To test my hypothesis, I have generated a range of useful reagents to study LPP3, including a recombinant lentivirus for efficient expression in vascular cells, engineered micro RNAs that target the mRNA of this protein for degradation, and transgenic mice that lack LPP3 in vascular smooth muscle cells. In Specific Aim One, I will test my hypothesis to elucidate the role of LPP3 in the regulation of vascular SMCs function in vitro. In Specific Aim Two, I will test my hypothesis by defining the role of LPP3 in regulation of vascular SMC function in response to injury. My results should provide specific insight into signaling systems mediated by LPA and may provide novel targets for treatment and prevention of vascular disorders.