{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nS1PR1 is a critical mediator of vascular development and homeostasis. It is essential for proper blood vessel formation by promoting endothelial cell survival, migration, and the recruitment of mural‐cells during embryogenesis – its genetic deletion results in defective vascular maturation and embryonic hemorrhage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the adult vasculature, activation of S1PR1 by its natural ligand sphingosine‐1‐phosphate (S1P) – and by protease–activated pathways such as those initiated by activated protein C – triggers intracellular events (e.g. Rac activation, PI3K–Akt signaling) that enhance endothelial barrier integrity and limit pathological permeability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, S1PR1 engagement regulates cytoskeletal rearrangements downstream of cues such as high–molecular–weight hyaluronan, thus contributing not only to barrier recovery but also to restricted, controlled angiogenic sprouting."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Additional studies show that S1PR1 signaling attenuates aberrant angiogenesis and inflammation, as evidenced by its role in maintaining proper vessel patterning and by its responsiveness to factors in oxidized lipid microdomains."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": " Furthermore, mechanisms that preserve receptor surface expression—such as HDL–bound S1P promoting sustained S1PR1 signaling—and that protect against inflammatory endothelial injury have been documented."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the immune compartment S1PR1 plays a pivotal role in regulating lymphocyte trafficking and function. Its finely tuned expression—modulated in part by post–translational phosphorylation events that dictate receptor internalization"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "—ensures proper T cell egress from lymphoid organs, as well as homeostatic control of proliferation and cytokine production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " S1PR1‐dependent signals also contribute to the homing of hematopoietic progenitor cells"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "and are targeted by immunomodulators such as FTY720 that shift lymphocyte distribution."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " In addition, transcriptional control by factors like FOXO1 helps maintain appropriate S1PR1 levels"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", while specific receptor phosphorylation (e.g. at S351) further modulates downstream signaling relevant to T helper cell polarization."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " Collectively, these pathways are critical for the regulation of immune cell egress and function in both homeostatic and inflammatory settings, as further illustrated by studies demonstrating that pharmacologic modulation of S1PR1 can alter disease progression in experimental autoimmune encephalomyelitis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its vascular‐ and immune–regulatory functions, S1PR1 signaling intersects with pathways governing cell migration, survival, and tissue remodeling in diverse contexts. In the central nervous system, modulation of S1PR1 by agents such as FTY720 influences oligodendrocyte progenitor cell process extension and differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "22"}]}, {"type": "t", "text": " Paradoxically, exposure to atypical agonists like FTY720–phosphate provokes S1PR1 phosphorylation and subsequent receptor degradation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": ", an effect that may contribute to its immunosuppressive actions as evidenced in oligodendrocyte lineage cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": " In oncology, elevated S1PR1 expression and its integration into oncogenic signaling pathways—such as the activation of STAT3 in breast cancer and lymphoma—correlate with poorer patient outcomes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "27"}]}, {"type": "t", "text": " S1PR1 further participates in the formation of signaling complexes with receptor tyrosine kinases (for example, the PDGFβ receptor), thereby enhancing cellular migratory responses that may also promote fibrotic changes in the liver."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " In the nervous system, S1PR1‐mediated pro–survival signaling has been linked to preservation of neuronal integrity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Y Liu, R Wada, T Yamashita, et al. 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