Biology subjects

Triebel, J.

Publications and source records attributed to Triebel, J..

4 recordsLinked to original sources

bioRxiv2024

The antiangiogenic peptide VIAN-c4551 inhibits lung melanoma metastasis in mice by reducing pulmonary vascular permeability

IntroductionCancer cells drive the increase in vascular permeability mediating tumor cell extravasation and metastatic seeding. VIAN-c4551, an antiangiogenic peptide analog of vasoinhibin, inhibits the growth and vascularization of melanoma tumors in mice. Because VIAN-c4551 is a potent inhibitor of vascular permeability, we evaluated whether its antitumor action extended to a reduction in metastasis generation. MethodsCirculating levels of vascular endothelial growth factor (VEGF), lung vascular permeability, melanoma cell extravasation, and melanoma pulmonary nodules were assessed in C57BL/6J mice intravenously inoculated with murine melanoma B16-F10 cells after acute treatment with VIAN-c4551. VEGF levels, transendothelial electrical resistance, and transendothelial migration in cocultures of B16-F10 cells and endothelial cell monolayers supported the findings. ResultsB16-F10 cells increased circulating VEGF levels and elevated lung vascular permeability 2 hours after inoculation. VIAN-c4551 prevented enhanced vascular permeability and reduced melanoma cell extravasation after 2 hours and the number and size of macroscopic and microscopic melanoma tumors in lungs after 17 days. In vitro, VIAN-c4551 suppressed the B16-F10 cell-induced and VEGF mediated increase in endothelial cell monolayer permeability and the transendothelial migration of B16-F10 cells. ConclusionsThese findings support the inhibition of distant vascular permeability for the prevention of tumor metastasis and unveil the anti-vascular permeability factor VIAN-c4551 as a potential therapeutic drug able to prevent metastasis generation by lowering the extravasation of melanoma cells.

cancer biology↗

bioRxiv2024

Vasoinhibin is Generated by the Renin-Angiotensin System

Vasoinhibin is a fragment of the hormone prolactin (PRL) that inhibits angiogenesis, vasopermeability, and vasodilation. Cathepsin D (CTSD) cleaves the N-teminal of PRL to generate vasoinhibin in the retina of neonate mice as revealed by the CTSD inhibitor, pepstatin A (PA). However, PA also inhibits renin. Because renin is expressed in the retina and the renin-angiotensin system (RAS) gives rise to peptides with positive and negative effects on blood vessel growth and function, we investigated whether renin cleaves PRL to vasoinhibin in the newborn mouse retina and in the circulation. Newborn mouse retinal extracts from wild-type and CTSD-null newborn mice cleaved PRL to a 14 kDa vasoinhibin and such cleavage was prevented by heat-inactivation, PA, and the selective renin inhibitor VTP-27999 suggesting the contribution of renin. In agreement, recombinant renin cleaved different species PRLs to the expected 14 kDa vasoinhibin, a mass consistent with a consensus renin cleavage site located at Leu124-Leu125 in rat and mouse PRLs and at Leu126-Leu127 in human, bovine, and ovine PRLs. Dehydration and rehydration (D/R) in rats increased the levels of renin and PRL in plasma. Further increase in PRL circulating levels by the dopamine D2 receptor blocker, sulpiride, enabled detection of 14 kDa vasoinhibin in D/R rats. Moreover, the incubation of PRL with plasma from D/R rats generated a 14 kDa vasoinhibin that was prevented by VTP-27999. These findings add renin to the list of PRL-cleaving proteases and introduce vasoinhibin as a RAS-mediated mechanism for regulating blood vessel growth and function.

physiology↗

bioRxiv2024

Topical Ophthalmic Administration of VIAN-c4551 Antiangiogenic Peptide for Diabetic Macular Edema: Preclinical Efficacy and Ocular Pharmacokinetics

VIAN-c4551 is a cyclic antiangiogenic peptide that stands as a potent and stable inhibitor of vascular endothelial cell growth factor (VEGF), the major vasopermeability and angiogenic factor in diabetic macular edema and diabetic retinopathy. Intravitreal injections of inhibitors of VEGF are a first-line therapy, but the invasiveness, risk, and low adherence of frequent intravitreal injections interfere with the needed long-term treatments and successful outcomes. Eye drops are non-invasive and favor compliance. Here, we evaluated the preclinical efficacy, permeability, and ocular pharmacokinetics of VIAN-c4551 delivered in eye drops. VIAN-c4551 demonstrated high potency (IC50 = 137 pM) to inhibit the permeability of human umbilical vein endothelial cell monolayers induced by VEGF. VIAN-c4551 eye drops potently (0.005% minimum effective dose) prevented the retinal vascular leakage induced by VEGF injected intravitreally for up to 24 hours and reversed the increase in retinal vascular permeability due to streptozotocin-induced diabetes in rats and mice. VIAN-c4551 exhibited high permeability across MDCK epithelium and, after a single topical ocular instillation in rabbits, reached the retina-choroid in micromolar concentrations several orders of magnitude above its IC50 (Cmax= 51 {micro}M at 6 hours) that lasted at least 24 hours. In conclusion, VIAN-c4551 eye drops reach the back of the eye at therapeutic concentrations, providing a potential, once-a-day, non-invasive intervention for preventing and reversing retinal vascular leakage in diabetic macular edema, diabetic retinopathy, and other vascular retinopathies and preserving sight.

pharmacology and toxicology↗

bioRxiv2023

The apoptotic, inflammatory, and fibrinolytic actions of vasoinhibin are in a motif different from its antiangiogenic HGR motif

Vasoinhibin is a proteolytic fragment of the hormone prolactin that inhibits blood vessel growth (angiogenesis) and permeability, stimulates the apoptosis and inflammation of endothelial cells and promotes fibrinolysis. The antiangiogenic and antivasopermeability properties of vasoinhibin were recently traced to the HGR motif located in residues 46 to 48, allowing the development of potent, orally active, HGR-containing vasoinhibin analogs for therapeutic use against angiogenesis-dependent diseases. However, whether the HGR motif is also responsible for the apoptotic, inflammatory, and fibrinolytic properties of vasoinhibin has not been addressed. Here, we report that HGR-containing analogs are devoid of these properties. Instead, the incubation of human umbilical vein endothelial cells with oligopeptides containing the sequence HNLSSEM, corresponding to residues 30 to 36 of vasoinhibin, induced apoptosis, the nuclear translocation of NF-{kappa}B, the expression of genes encoding leukocyte adhesion molecules (VCAM1 and ICAM1) and proinflammatory cytokines (IL1B, IL6, TNF), and the adhesion of peripheral blood leukocytes. Also, the intravenous or intra-articular injection of HNLSSEM-containing oligopeptides induced the expression of Vcam1, Icam1, Il1b, Il6, Tnf in the lung, liver, kidney, eye, and joints of mice and, like vasoinhibin, these oligopeptides promoted the lysis of plasma fibrin clots by binding to plasminogen activator inhibitor-1 (PAI-1). Moreover, the inhibition of PAI-1, urokinase plasminogen activator receptor, or NF-{kappa}B prevented the apoptotic and inflammatory actions. In conclusion, the functional properties of vasoinhibin are segregated into two different structural determinants. Because apoptotic, inflammatory, and fibrinolytic actions may be undesirable for antiangiogenic therapy, HGR-containing vasoinhibin analogs stand as selective and safe agents for targeting pathological angiogenesis.

cell biology↗