Circulating Lymphangiogenic Factors in Preeclampsia

Background. Preeclampsia (PE), a human pregnancy-specific disorder is characterized by an anti-angiogenic state due to high levels of circulating soluble vascular endothelial growth factor 1 (sVEGFR-1). However, the role of lymphangiogenesis in PE has not been investigated. Recently, impaired vascular endothelial growth factor C (VEGF-C) (factor that regulates lymphangiogenesis) signaling has been implicated in the pathogenesis of interstitial edema and salt-sensitive hypertension. Therefore, we hypothesized that circulating VEGF-C and its circulating receptors (sVEGFR-2 and sVEGFR-3) may also be altered in PE and correlate with the severity of the phenotype. Methods. We analyzed plasma levels of VEGF-C, sVEGFR-1, sVEGFR-2, and sVEGFR-3 in women with gestational hypertension (GHTN, n = 20), PE (n = 20), and normotensive pregnancies (NP, n = 20) in the third trimester and values were reported as mean +/- SD in pg/mL. Results. As previously reported, sVEGFR-1 levels were significantly higher in subjects with PE (19,938 +/- 12,973) than in GHTN (7156 +/- 5432), p <0.01 or NP (7760 +/- 6018), p <0.01. VEGF-C levels were lower in subjects with GHTN (676 +/- 323) than in PE (1335 +/- 625), p <0.01, but not statistically different than inNP (971 +/- 556), p 0.11. There was a trend toward lower sVEGFR-2 in PE as compared to GHTN or NP. Interestingly, sVEGFR-3 was significantly lower in PE (54,371 +/- 21,107) as compared to NP (83,709 +/- 24,983), p <0.01, but not different as compared to GHTN (54,642 +/- 26,947). The ratio of sVEGFR-2 + sVEGFR-3/VEGF-C was dramatically lower during PE (57 +/- 38) as compared to GHTN (113 +/- 72), p <0.01 or NP (133 +/- 91), p <0.01. Conclusions. PE is characterized by circulating pro-lymphangiogenic state as evidenced by decreased sVEGFR-3, slightly decreased sVEGFR-2, increased VEGF-C, and a dramatically lower ratio of sVEGFR-2 + sVEGFR-3/VEGF-C. Our data suggest that the circulating pro-lymphangiogenic state during PE may be a compensatory response to edema and hypertension. Additional studies are needed to evaluate the clinical relevance of the altered lymphangiogenic signaling pathway during PE.