Key result
HIF-2α stabilization resulting from PHD2/PHD3 deletion in preglomerular vascular smooth muscle cells triggers erythropoietin production rather than renin upon stimulation.
Why the study?
It was unknown whether prolyl-4-hydroxylases 2 and 3 regulate the endocrine plasticity of preglomerular vascular smooth muscle cells.
HIF-2α stabilization via PHD2/PHD3 deletion shifts the endocrine plasticity of preglomerular VSMCs from renin to EPO production under stimulatory conditions.
No immediate clinical implications for PHD inhibitor therapy; leaves open differential endocrine plasticity between renin cells and preglomerular VSMCs.
Renal 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.
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Firmke et al. (2026) studied Endocrine plasticity of preglomerular vascular smooth muscle cells. SMMHC-specific deletion of PHD2 and/or PHD3 with low-salt diet and enalapril vs. Control mice was evaluated on Renin and erythropoietin production in preglomerular pericyte-like VSMCs. HIF-2α stabilization resulting from PHD2/PHD3 deletion in preglomerular vascular smooth muscle cells triggers erythropoietin production rather than renin upon stimulation.
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