{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRGS5 is a critical negative regulator of G protein–coupled receptor (GPCR) signaling that plays diverse roles in vascular homeostasis and remodeling. It is selectively induced in activated pericytes during both physiologic and pathologic angiogenesis—such as in tumor‐associated and healing vessels—serving as an important marker of “activated” pericytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In endothelial cells, RGS5 is robustly upregulated under hypoxic conditions, where it modulates VEGF‐mediated signaling and promotes apoptosis, thereby contributing to vessel remodeling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In the heart, RGS5 limits maladaptive remodeling by inhibiting MAP kinase cascades such as the MEK–ERK pathway"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": ", whereas in vascular smooth muscle cells it attenuates pro‐contractile and proliferative signaling that leads to neointima formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Furthermore, in brain pericytes RGS5 is rapidly stabilized during hypoxia to desensitize chemotactic signals from factors like PDGF‐BB and sphingosine 1‐phosphate"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", and structural studies have illuminated its function as a GTPase–activating protein that accelerates Gα hydrolysis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Its expression in dental pulp and perivascular soft tissue tumors further underscores its value as a pericyte marker for reparative processes and diagnostic pathology"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", and RGS5 also attenuates signaling downstream of PAR1 activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in RGS5 expression have significant implications in cancer biology. In ovarian carcinoma, increased RGS5 levels in tumor vasculature correlate with lower microvascular density and improved progression‐free survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In contrast, in non–small cell lung cancer, RGS5 overexpression has been shown to induce apoptosis, reduce adhesion and migration, and enhance radiosensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In squamous cell carcinoma of the tongue, elevated RGS5 associates with more aggressive invasion, epithelial–mesenchymal transition, and early lymph node metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In breast cancer, a long noncoding RNA overlapping the RGS5 locus (lnc‐RGS5) promotes tumor cell proliferation through sponging microRNA‐542–5p and upregulating oncogenic effectors such as FOXM1 and VEGFA/Neuropilin 1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": ", and elevated RGS5 transcripts in lymphomas point to a broader role in hematologic malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and regulatory studies further underscore the clinical significance of RGS5 across a range of disorders. Genetic variants in RGS5 have been linked to bipolar disorder"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": ", as well as to essential hypertension in different populations"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "21"}]}, {"type": "t", "text": ", while elevated RGS5 expression in parathyroid adenomas suggests a role in disrupting calcium-sensing receptor signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " Furthermore, diminished RGS5 expression in airway smooth muscle following chronic β₂-agonist exposure can enhance procontractile signaling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", and emerging evidence implicates RGS5 in the pathogenesis of nonalcoholic fatty liver disease"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "as well as in coronary artery disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": " In neuropsychiatric contexts, RGS5 along with other family members may contribute to schizophrenia susceptibility"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": ", while studies comparing the intrinsic potency of RGS proteins indicate that RGS5 may exhibit modest inhibitory activity under certain conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": " Population genetic analyses have also linked RGS5 variants with blood pressure regulation in distinct ethnic cohorts"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": ", and its role in modulating atrial muscarinic receptor-activated currents further suggests involvement in cardiac excitability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mario Berger, Gabriele Bergers, Bernd Arnold, et al. 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