Current medicinal chemistry · 2026
Therapeutic Effects of Phosphodiesterase Inhibitors on Hypertensive Disorders in Pregnancy and Fetal Growth Restriction: A Drug Targeted Mendelian Randomization Study.
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Xia Dandan, Li Siyu, Liu Wenjie, Zhang Yuhui, Zhang Chenying, She Guangtong, Wang Huiyan
Аннотация
OBJECTIVE: Phosphodiesterases (PDEs) are considered promising drug targets due to their close association with various pathological and physiological processes. We aimed to investigate the causal relationship between PDE inhibitors and hypertensive disorders of pregnancy (HDP) and fetal growth restriction (FGR).
METHODS: We used expression quantitative trait loci (eQTLs) related to PDEs as surrogate indicators of PDE gene expression levels and conducted single-sample Mendelian randomization (SMR) analysis and two-sample MR validation through the pharmacological target.
RESULTS: SMR analysis showed that PDE4B, PDE5A, PDE8A, and PDE9A were associated with pregnancy outcomes. Two-sample MR validation revealed that PDE5A in blood was negatively correlated with the occurrence of FGR (OR = 0.91, CI = 0.81-1.00, p = 0.045), while PDE4B was a risk factor for gestational hypertension (GH) (OR = 1.24, 95% CI = 1.09-1.39, p = 0.006). We performed SMR analysis again using protein quantitative trait loci (pQTLs) related to PDE5A as a surrogate for PDE5A protein levels, and the results showed no significant association between PDE5A and HDP or FGR. Further validation of the causal relationship between PDE4B and GH using a two-step MR approach revealed that PDE4B promotes the occurrence of GH through multiple metabolic factors.
DISCUSSION: Our MR results prioritize PDE4B, but not PDE5A, as a causal driver of GH, offering genetically anchored justification for repositioning selective PDE4B inhibitors in pregnancy. Protective signals for PDE5A on fetal growth require tissue-level confirmation and cautious dose-finding before any clinical re-evaluation.
CONCLUSION: PDE5A is not a potential therapeutic target for HDP and FGR, while PDE4B is closely related to the occurrence of GH. This suggests that PDE4B inhibitors may have therapeutic potential for GH and provides an important reference for the treatment of HDP and FGR.
METHODS: We used expression quantitative trait loci (eQTLs) related to PDEs as surrogate indicators of PDE gene expression levels and conducted single-sample Mendelian randomization (SMR) analysis and two-sample MR validation through the pharmacological target.
RESULTS: SMR analysis showed that PDE4B, PDE5A, PDE8A, and PDE9A were associated with pregnancy outcomes. Two-sample MR validation revealed that PDE5A in blood was negatively correlated with the occurrence of FGR (OR = 0.91, CI = 0.81-1.00, p = 0.045), while PDE4B was a risk factor for gestational hypertension (GH) (OR = 1.24, 95% CI = 1.09-1.39, p = 0.006). We performed SMR analysis again using protein quantitative trait loci (pQTLs) related to PDE5A as a surrogate for PDE5A protein levels, and the results showed no significant association between PDE5A and HDP or FGR. Further validation of the causal relationship between PDE4B and GH using a two-step MR approach revealed that PDE4B promotes the occurrence of GH through multiple metabolic factors.
DISCUSSION: Our MR results prioritize PDE4B, but not PDE5A, as a causal driver of GH, offering genetically anchored justification for repositioning selective PDE4B inhibitors in pregnancy. Protective signals for PDE5A on fetal growth require tissue-level confirmation and cautious dose-finding before any clinical re-evaluation.
CONCLUSION: PDE5A is not a potential therapeutic target for HDP and FGR, while PDE4B is closely related to the occurrence of GH. This suggests that PDE4B inhibitors may have therapeutic potential for GH and provides an important reference for the treatment of HDP and FGR.