Important Endothelial Mediator Independent of Endothelial Nitric Oxide Synthase

Tetrahydrobiopterin (BH4), an essential cofactor for diverse cellular processes, is present in almost every cell or tissue of higher organisms. BH4 has well-defined functions in terms of enzymatic activities (BH4 is a crucial cofactor for the aromatic amino acid hydroxylases and all isoforms of nitric oxide synthase [NOS]) but has other less-defined functions in cells. BH4 is a growth or proliferation factor for various mammalian cells, including hematopoietic and endothelial cells.1,2 Epidermal growth factor and nerve growth factor act to increase proliferation of rat PC12 cells by elevating BH4 levels.3 However, BH4 is also a powerful antioxidant4 and has scavenging capabilities, reacting with superoxide anion radicals peroxynitrite and hydrogen peroxide.5 BH4 bioavailability is, thus, potently influenced by oxidative stress in cells. GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase, and sepiapterin reductase act in sequence to generate BH4 de novo in endothelial cells.5 The first enzyme, GTPCH, is thought to be the rate-controlling enzyme. GTPCH activity can be controlled at the transcriptional level by a number of mediators, including nutritional (phenylalanine and arginine), hormonal (insulin and estrogen), immunologic (inflammatory cytokines including interleukin1, interferon, and tumor necrosis factor), therapeutic (statins and cyclosporin A), and endothelium-derived (basic fibroblast growth factor and H2O2) factors.5 These agonists act via different mechanisms but all lead to the increased generation of BH4. BH4 regulates NO synthesis in both mature endothelial cells and endothelial progenitor cells (EPCs). Bone marrow– derived EPCs have the potential to give rise to circulating vascular progenitor cells that home to damaged vessels and differentiate into mature endothelial cells, thereby contributing to vascular repair, remodeling, and maintenance of endothelial function. Mobilization and recruitment of these cells, for example, play a key role in postischemic tissue repair. EPCs isolated from bone marrow aspirates or peripheral blood can be reintroduced into the circulation or ischemic tissue where they participate in blood vessel growth at sites of ischemia or vessel injury and improve blood circulation in ischemic disease. A growing number of studies have investigated the feasibility of using autologous EPCs to induce therapeutic revascularization and tissue repair in patients with a variety of ischemic conditions. Unfortunately, the vascular regenerative potential of EPCs is impaired in some disease conditions, such as hypertension or diabetes mellitus. This impairment is manifested as reduced EPC number and function. Interestingly, hyperglycemia-induced EPC dysfunction can be reversed by treating EPCs with BH4. In this issue of Hypertension, He et al6 report that the ligand-activated transcription factor peroxisome proliferator-activated receptor– (PPAR ) enhances the regenerative capacity of human EPCs by stimulating BH4 biosynthesis. Using the high-affinity ligand for PPAR , GW501516, these authors demonstrate that PPAR activation increases EPC proliferation and migration by stimulating phosphoinositide 3-kinase/AKT/GTPCH–mediated BH4 synthesis and reducing PTEN-mediated dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate, which would decrease activation of AKT. The proproliferative effect of PPAR activation is abolished by inhibiting GTPCH activity but not by inhibiting endothelial NOS (eNOS) activity, illustrating that BH4 has direct effects on EPC proliferation that are independent of its ability to enhance NO synthesis (Figure). These human EPCs helped to repair denuded endothelium in a mouse model of carotid injury. Pretreatment with GW501516 or GTPCH knockdown significantly enhanced or inhibited, respectively, the re-endothelialization brought about by injected EPCs. Our understanding of the role of PPAR in vascular cells is limited. In this study, He et al6 demonstrate that PPAR activation can regulate AKT signaling in EPCs by decreasing PTEN action, effectively reducing PTEN s antagonism of the phosphoinositide 3-kinase pathway, increasing AKT activation, and boosting the production of BH4 via GTPCH.6 This effect of PPAR appears to be direct and not attributed to activation of the phosphoinositide 3-kinase-Akt-nuclear factor B pathway. However, this does not rule out other indirect mechanisms to support GTPCH activity in EPCs, such as activation of AMP-activated protein kinase. Wang et al7 demonstrated that activation of AMP-activated protein kinase The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Systems Biology and Translational Medicine (C.J.M., G.W.), Texas A&M Health Science Center, Temple, TX; Department of Animal Science (G.W.), Texas A&M University, College Station, TX. Correspondence to Cynthia J. Meininger, 702 SW H.K. Dodgen Loop, MRB 138, Texas A&M Health Science Center, Temple, TX 76504. E-mail [email protected] (Hypertension. 2011;58:145-147.) © 2011 American Heart Association, Inc.