Biomedicines

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21 pages, 3657 KiB

Open AccessArticle

Scandium-44 Radiolabeled Peptide and Peptidomimetic Conjugates Targeting Neuropilin-1 Co-Receptor as Potential Tools for Cancer Diagnosis and Anti-Angiogenic Therapy

by Katarzyna Masłowska, Patrycja Redkiewicz, Paweł Krzysztof Halik, Ewa Witkowska, Dagmara Tymecka, Rafał Walczak, Jarosław Choiński, Aleksandra Misicka and Ewa Gniazdowska

Biomedicines 2023, 11(2), 564; https://doi.org/10.3390/biomedicines11020564 - 15 Feb 2023

Cited by 1 | Viewed by 1672

Abstract

Pathological angiogenesis, resulting from an imbalance between anti- and pro-angiogenic factors, plays a pivotal role in tumor growth, development and metastasis. The inhibition of the angiogenesis process by the VEGF/VEGFR-2/NRP-1 pathway raises interest in the search for such interaction inhibitors for the purpose [...] Read more.

Pathological angiogenesis, resulting from an imbalance between anti- and pro-angiogenic factors, plays a pivotal role in tumor growth, development and metastasis. The inhibition of the angiogenesis process by the VEGF/VEGFR-2/NRP-1 pathway raises interest in the search for such interaction inhibitors for the purpose of the early diagnosis and treatment of angiogenesis-dependent diseases. In this work we designed and tested peptide-based radiocompounds that selectively bind to the neuropilin-1 co-receptor and prevent the formation of the pro-angiogenic VEGF-A₁₆₅/NRP-1 complex. Three biomolecules, A7R and retro-inverso ^DR7A peptides, and the branched peptidomimetic Lys(hArg)-Dab-Pro-Arg (K4R), conjugated with macrocyclic chelator through two linkers’ types, were labeled with theranostic scandium-44 radionuclide, and studied in vitro as potential targeted radiopharmaceuticals. ELISA (enzyme-linked immunosorbent assay) studies showed no negative effect of the introduced biomolecules’ changes and high NRP-1 affinity in the case of A7R- and K4R-radiocompounds and a lack affinity for ^DR7A-radiocompounds. All radiopeptides showed a hydrophilic nature as well as high stability against ligand exchange reactions in cysteine/histidine solutions. Unfortunately, all radiocompounds showed unsatisfactory nano-scale stability in human serum, especially for use as therapeutic radioagents. Further work is ongoing and focused on the search for angiogenesis inhibitors that are more human serum stable. Full article

(This article belongs to the Special Issue Angiogenesis in Health and Disease)

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11 pages, 1264 KiB

Open AccessArticle

TGFβ1 Induces Senescence and Attenuated VEGF Production in Retinal Pericytes

by Dragana Avramovic, Sébastien A. Archaimbault, Alicia M. Kemble, Sabine Gruener, Mirjana Lazendic and Peter D. Westenskow

Biomedicines 2022, 10(6), 1404; https://doi.org/10.3390/biomedicines10061404 - 14 Jun 2022

Cited by 2 | Viewed by 2413

Abstract

Diabetic retinopathy (DR) is a microvascular disease of the retina and a serious complication of type I and type II diabetes mellitus. DR affects working-age populations and can cause permanent vision loss if left untreated. The standard of care for proliferative DR is [...] Read more.

Diabetic retinopathy (DR) is a microvascular disease of the retina and a serious complication of type I and type II diabetes mellitus. DR affects working-age populations and can cause permanent vision loss if left untreated. The standard of care for proliferative DR is inhibiting VEGF. However, the mechanisms that induce excessive VEGF production in the retina remain elusive, although some evidence links elevated VEGF in the diabetic retina with local and systemic TGFβ1 upexpression. Here, we present evidence from animal models of disease suggesting that excessive TGFβ1 production in the early DR is correlated with VEGF mRNA and protein production by senescent pericytes and other retinal cells. Collectively, these results confirm that TGFβ1 is strongly implicated in the vascular complications of DR. Full article

(This article belongs to the Special Issue Angiogenesis in Health and Disease)

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20 pages, 5614 KiB

Open AccessArticle

Identification of Novel Vascular Genes Downstream of Islet2 and Nr2f1b Transcription Factors

by Ru-Fang Li, Yi-Shan Wang, Fu-I Lu, Yi-Shan Huang, Chien-Chih Chiu, Ming-Hong Tai and Chang-Yi Wu

Biomedicines 2022, 10(6), 1261; https://doi.org/10.3390/biomedicines10061261 - 27 May 2022

Cited by 2 | Viewed by 1859

Abstract

The genetic regulation of vascular development is not elucidated completely. We previously characterized the transcription factors Islet2 (Isl2) and Nr2f1b as being critical for vascular growth. In this study, we further performed combinatorial microarrays to identify genes that are potentially regulated by these [...] Read more.

The genetic regulation of vascular development is not elucidated completely. We previously characterized the transcription factors Islet2 (Isl2) and Nr2f1b as being critical for vascular growth. In this study, we further performed combinatorial microarrays to identify genes that are potentially regulated by these factors. We verified the changed expression of several targets in isl2/nr2f1b morphants. Those genes expressed in vessels during embryogenesis suggested their functions in vascular development. We selectively assayed a potential target follistatin a (fsta). Follistatin is known to inhibit BMP, and BMP signaling has been shown to be important for angiogenesis. However, the fsta’s role in vascular development has not been well studied. Here, we showed the vascular defects in ISV growth and CVP patterning while overexpressing fsta in the embryo, which mimics the phenotype of isl2/nr2f1b morphants. The vascular abnormalities are likely caused by defects in migration and proliferation. We further observed the altered expression of vessel markers consistent with the vascular defects in (fli:fsta) embryos. We showed that the knockdown of fsta can rescue the vascular defects in (fli:fsta) fish, suggesting the functional specificity of fsta. Moreover, the decreased expression of fsta rescues abnormal vessel growth in isl2 and nr2f1b morphants, indicating that fsta functions downstream of isl2/nr2f1b. Lastly, we showed that Isl2/Nr2f1b control vascular development, via Fsta–BMP signaling in part. Collectively, our microarray data identify many interesting genes regulated by isl2/nr2f1b, which likely function in the vasculature. Our research provides useful information on the genetic control of vascular development. Full article

(This article belongs to the Special Issue Angiogenesis in Health and Disease)

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