RESUMO
PURPOSE OF REVIEW: Hydrogen sulfide (H2S), a colorless gas that is endogenously generated in mammals from cysteine, has important biological functions. Within the vasculature it regulates vessel tone and outgrowth of new vessels. This review summarizes recent literature on H2S signaling in the vasculature and its therapeutic potential in vascular disorders RECENT FINDINGS: H2S is able to induce vasorelaxation via ATP-sensitive potassium channels in vascular smooth muscle cells. Large-conductance calcium-dependent K+-channels and Kv7 voltage-gated K+-channels are also involved in H2S signaling. Vascular endothelial growth factor is the key downstream mediator that is involved in H2S induced angiogenesis. By having both direct effects on its receptor and increasing the bioavailability of vascular endothelial growth factor, H2S is proangiogenic. H2S-based therapies in vascular diseases are an expanding area of research. The applications of several compounds, such as natural donors and synthetic slow release compounds, have been extensively studied in vascular diseases such as hypertension, ischemia-reperfusion disorders and preeclampsia. SUMMARY: 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.
Assuntos
Sulfeto de Hidrogênio/farmacologia , Hipertensão/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Pré-Eclâmpsia/tratamento farmacológico , Vasodilatação/efeitos dos fármacos , Animais , Feminino , Humanos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , GravidezRESUMO
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 µmol/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.
Assuntos
Sulfeto de Hidrogênio/farmacologia , Hipertensão/tratamento farmacológico , Proteinúria/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/fisiologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/fisiologia , Animais , Feminino , Glomérulos Renais/efeitos dos fármacos , Podócitos/metabolismo , Ratos , Ratos Sprague-Dawley , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/genética , Vasodilatação/efeitos dos fármacosRESUMO
OBJECTIVES: Preeclampsia (PE) is a pregnancy complication, characterized by hypertension and proteinuria. The transsulfuration pathway may be involved in its pathophysiology, since homocysteine, cystathionine and cysteine are increased in PE. Cystathionine-ß-synthase (CBS) is a key-enzyme in the pathway, converting homocysteine into cysteine via cystathionine. Another product of CBS is hydrogen sulfide (H2S), a vasodilatory, proangiogenic and cytoprotective gas that is thought to play a role in placental and vascular function during pregnancy. Since single nucleotide polymorphisms (SNPs) can affect CBS expression and/or function, we studied tag-SNPs in the CBS gene in PE patients. STUDY DESIGN: Controls (n=75), early-onset (n=45), and late-onset PE (n=52) cases were genotyped for six tag-SNPs in the CBS gene; rs12329764, rs2851391, rs234713, rs234706, rs1789953, and rs11203172. Plasma homocysteine, cysteine and cystathionine were determined during pregnancy. MAIN OUTCOME MEASURES: Early-onset PE, late-onset PE. RESULTS: Women with the minor allele of rs11203172 have a reduced risk for early-onset PE. Compared to women without the minor allele, normotensive pregnant women with the minor allele of rs11203172 and rs234713 have lower cysteine levels. Women with the minor allele of rs1789953 have increased levels of cysteine and cystathionine, compared to women without. CONCLUSION: The CBS tag-SNP rs11203172 is associated with a decreased risk for early-onset PE. Decreased cysteine concentrations in normotensive pregnant women carrying the minor allele of rs11203172, may be due to increased cysteine conversion to H2S by CBS. Higher H2S levels may positively affect placentation and vascular function during pregnancy and decrease their risk for PE.
Assuntos
Pressão Sanguínea/genética , Cistationina beta-Sintase/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Cistationina/sangue , Cistationina beta-Sintase/metabolismo , Cisteína/sangue , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Idade Gestacional , Homocisteína/sangue , Humanos , Fenótipo , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/enzimologia , Gravidez , Fatores de Proteção , Fatores de RiscoRESUMO
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 in NP (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.