["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Preglomerular pericyte‐like SMMHC+ vascular smooth muscle cells (VSMCs) display marked endocrine plasticity. Hypotension caused by salt depletion and angiotensin‐converting enzyme (ACE) inhibition induces a reversible transformation of these VSMCs toward an endocrine state that produces renin. Chronic HIF‐2α stabilization – by SMMHC‐specific PHD2/PHD3 deletion – reprograms the VSMCs from a contractile/renin cell‐like toward a more contractile/erythropoietin (EPO) cell‐like transcriptional signature, yet without inducing EPO synthesis. Under these conditions, hypotension triggers a reversible switch to an endocrine state that produces EPO instead of renin. In the closely related SMMHC+ interstitial contractile pericytes, deletion of PHD2 or combined PHD2/PHD3 loss induces HIF‐2α‐dependent EPO production in the subset of solely PHD2+ pericytes or in both PHD2+ and PHD2/3+ pericytes, respectively, independent of systolic blood pressure. Overall, PHD2 and PHD3 determine the endocrine output of preglomerular VSMCs and interstitial pericytes by regulating HIF‐2α, while their loss does not impair the plasticity of VSMCs to reversibly adopt endocrine functions. Created with BioRender.com.\n\n\n\n\n\n\n\n\n\nAbstract\nRenal juxtaglomerular renin‐producing cells and preglomerular vascular smooth muscle cells (VSMCs) are specialized pericytes with notable plasticity. Preglomerular VSMCs can convert to renin‐producing cells during severe hypotension or salt depletion, and renin cells can transform into erythropoietin (EPO)‐producing cells when hypoxia‑inducible factor (HIF)‐2α is stabilized through deletion of prolyl‐4‐hydroxylases (PHD) 2 and 3. These findings raise the question of whether PHD2 and PHD3 likewise regulate the endocrine plasticity of preglomerular VSMCs. To investigate the role of PHD2 and/or PHD3 in (preglomerular) contractile pericytes, inducible mouse models with smooth muscle myosin heavy chain (SMMHC)‐specific deletion of PHD2 and/or PHD3 were examined under basal conditions or after stimulation of renin production by treating the mice with a low‐salt diet and angiotensin converting enzyme inhibitor enalapril (LSE). At baseline, none of the deletions altered renin production or induced EPO expression in preglomerular pericyte‐like VSMCs, despite HIF‐2α stabilization in PHD2/PHD3‐deficient mice. However, HIF‐2α stabilization resulting from PHD2 or PHD2/PHD3 deletion triggered EPO production in interstitial SMMHC+ contractile pericytes. LSE treatment induced renin in VSMCs and extraglomerular mesangial cells of control, SMMHCCreERT2 PHD2ff and SMMHCCreERT2 PHD3ff mice. In contrast, VSMCs of PHD2/PHD3‐deficient mice produced EPO rather than renin, while renin induction persisted only in mesangial cells. Notably, this LSE‐induced EPO production was reversible despite ongoing HIF‐2α stabilization. Transcriptional changes indicated a shift in PHD2/PHD3‐deficient VSMCs from a contractile/renin cell‐like to a contractile/EPO cell‐like signature. These findings indicate that HIF‐2α stabilization determines the endocrine product of preglomerular VSMCs and interstitial pericytes. Notably, loss of PHD2/PHD3 does not compromise the plasticity of VSMCs to reversibly adopt endocrine functions.\n\n\n\n\n\n\n\n\n\nKey points\n\nSmooth muscle myosin heavy chain (SMMHC)‐specific deletion of the prolyl‑4‑hydroxylases PHD2 and PHD3 stabilized hypoxia‑inducible factor (HIF)‑2α in preglomerular pericyte‑like vascular smooth muscle cells (VSMCs), prompting a transcriptional shift from a contractile/renin cell‑like toward a more contractile/EPO cell‑like signature without activating erythropoietin (EPO) transcription.\nA reduction in systolic blood pressure through treatment with low‐salt diet and angiotensin converting enzyme inhibitor enalapril induced EPO synthesis instead of renin in preglomerular PHD2/PHD3‐deficient VSMCs. Transformation of preglomerular VSMCs into EPO‐producing cells was reversible despite persistent HIF‐2α stabilization.\nSMMHC cell‐specific deletion of PHD2 and PHD2/PHD3 activated EPO production in interstitial contractile pericytes independent of systolic blood pressure.\nShort‑term HIF‑2α stabilization was insufficient to induce EPO production in preglomerular VSMCs or contractile pericytes.\nΤaken together these findings demonstrate that HIF‐2α stabilization governs the endocrine output of preglomerular VSMCs and interstitial pericytes. Notably, the loss of PHD2/PHD3 does not impair the capacity of VSMCs to reversibly assume endocrine functions.\n\n\n"]