Soluble fms-like tyrosine kinase 1 (sFlt1), a circulating antiangiogenic protein, is elevated in kidney diseases and contributes to the development of preeclampsia. Hydrogen sulfide is a vasorelaxant and proangiogenic gas with therapeutic potential in several diseases. Therefore, we evaluated the potential therapeutic effect and mechanisms of action of hydrogen sulfide in an animal model of sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis created by adenovirus-mediated overexpression of sFlt1 in Sprague-Dawley rats. We injected sFlt1-overexpressing animals intraperitoneally with the hydrogen sulfide-donor sodium hydrosulfide (NaHS) (50 mmol/kg, twice daily) or vehicle (n=7 per group). Treatment with NaHS for 8 days significantly reduced sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis. Measurement of plasma protein concentrations with ELISA revealed a reduction of free plasma sFlt1 and an increase of free plasma vascular endothelial growth factor (VEGF) after treatment with NaHS. Renal VEGF-A mRNA expression increased significantly with NaHS treatment. In vitro, NaHS was proangiogenic in an endothelial tube assay and attenuated the antiangiogenic effects of sFlt1. Stimulation of podocytes with NaHS resulted in both short-term VEGF release (120 minutes) and upregulation of VEGF-A mRNA levels (24 hours). Furthermore, pretreatment of mesenteric vessels with a VEGF receptor 2-neutralizing antibody significantly attenuated NaHS-induced vasodilation. These results suggest that hydrogen sulfide ameliorates sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis in rats by increasing VEGF expression. Further studies are warranted to evaluate the role of hydrogen sulfide as a novel therapeutic agent for vascular disorders such as preeclampsia.

Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state. As hydrogen sulfide (H(2)S) has pro-angiogenic and anti-oxidative characteristics, we hypothesized that H(2)S levels could play a role in the pathogenesis of preeclampsia and studied the placental expression of the H(2)S-producing enzymes cystathionine-γ-lyase (CSE) and cystathionine-β-synthase (CBS). CBS and CSE protein are expressed in the fetal-placental endothelium and CBS only in Hofbauer cells. CBS mRNA expression is decreased (p = 0.002) in early-onset preeclampsia, while CSE mRNA is unchanged. Thus, down regulation of CBS during early-onset preeclampsia may result in less H(2)S-production and may aid in the anti-angiogenic state.

H2S has a key role in vascular homeostasis during physiology and in pathological states. H2S-based therapies may have a role in several vascular diseases.

Background Preeclampsia, 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 preeclampsia has not been investigated. Recently, impaired VEGF-C (factor that regulates lymphangiogenesis) signalling 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 preeclampsia 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), preeclampsia (PE, n=20) and normotensive pregnancies (NP, n=20) in the third trimester and values reported as mean ± SD in pg/ml. Results As previously reported, sVEGFR-1 levels were significantly higher in subjects with PE (19938 ± 12973) 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 in NP (971 ± 556), p=0.11. There was a trend towards lower sVEGFR-2 in PE as compared to GHTN or NP. Interestingly sVEGFR-3 was significantly lower in PE (54371 ± 21107) as compared to NP (83709 ± 24983), p<0.01, but not different as compared to GHTN (54642 ± 26947). 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. Conclusion Preeclampsia 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 suggests that the circulating pro-lymphoangiogenic state during preeclampsia may be a compensatory response to edema and hypertension. Additional studies are needed to evaluate the clinical relevance of the altered lymphangiogenic signalling pathway during preeclampsia.

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