Cheng Pre-Doc Fellowship: Signaling of LPA Receptors 1 and 2 is Vital for Regulation of Pulmonary Vascular Tone

Pulmonary vascular tone is determined by the balance between vasodilators and vasoconstrictors in the pulmonary circulation. Pulmonary hypertension is a common consequence when the balance fails, and will lead to pulmonary vasculature remodeling, right ventricular hypertrophy, and eventually, heart failure. Nitric Oxide (NO), synthesized by endothelial NO synthase (eNOS), is a potent vasodilator and has been shown to playa central role in maintaining the pulmonary vascular tone against various vasoconstrictive stimulants such as hypoxia. Mice genetically deficient of eNOS are hyperresponsive to hypoxia-induced pulmonary hypertension as well as right ventricular hypertrophy. However, the upstream regulatory mechanism of eNOS in pulmonary hypertension development is still inconclusive despite many attempts over the years. Lysophosphatidic acid (LPA) is a bioactive lipid mediator secreted by activated platelets that acts by binding to five G protein-coupled receptors (GPCRs), termed LPA 1-5. Several lines of evidence reveal that LPA activates eNOS in a receptor-dependent manner in cell cultures. Our preliminary work provides a possible link between LPA signaling and eNOS activation in a mouse model. We found that mice deficient of LPA receptors 1 and 2 develop elevated right ventricular pressure, right ventricular hypertrophy, and declined heart function over time, which resemble the phenotype of eNOS-knockout mice. Given that LPA is a potential eNOS activator, I hypothesize LPA promotes eNOS activity and NO production through LPA receptors 1 and 2 to maintain the normal pulmonary vascular resistance. Two specific aims will be tested. First, I will determine whether loss of LPA receptor 1 and 2 affect the susceptibility to hypoxia-triggered pulmonary hypertension. The working hypothesis is that LPA receptors 1 and 2 are required for eNOS-dependent pulmonary vasodilation, and hence deficiency of LPA receptors 1 and 2 will lead to hyperresponsiveness to hypoxia, which resembles the phenotype of the eNOS-deficient mice. Second, I will test the direct effect of LPA receptor 1 and 2 to eNOS activation in cultured pulmonary vascular endothelial cells. I will determine the expression level and overall activity of eNOS upon LPA stimulation, and anticipate to see the deficiency of LPA receptors 1 and 2 block LPA-induced eNOS activation. Together, our results are expected to gain insight of LPA's role in the regulation of pulmonary vascular tone.