Proangiogenic Activity Research Articles

Multiple crosslinked, self-healing, and shape-adaptable hydrogel laden with pain-relieving chitosan@borneol nanoparticles for infected burn wound healing.

Rationale: Next-generation wound dressings with multiple biological functions hold promise for addressing the complications and pain associated with burn wounds. Methods: A hydrogel wound dressing loaded with a pain-relieving drug was developed for treating infected burn wounds. Polyvinyl alcohol chemically grafted with gallic acid (PVA-GA), sodium alginate chemically grafted with 3-aminobenzeneboronic acid (SA-PBA), Zn2+, and chitosan-coated borneol nanoparticles with anti-inflammatory and pain-relieving activities were combined to afford a nanoparticle-loaded hydrogel with a PVA-GA/Zn2+/SA-PBA network crosslinked via multiple physicochemical interactions. Results: The developed hydrogel demonstrated adhesiveness, self-healing, shape adaptability, injectability, degradability, conformity to complicated wound surfaces, and other desirable biological functions, including a pH-responsive drug release behavior and antibacterial, antioxidant, anti-inflammatory, and proangiogenic activities. In a murine scald wound model, the hydrogel effectively prevented infection by Staphylococcus aureus and downregulated pain perception (measured using mouse grimace scale scores and hind paw lifting and licking times), thereby accelerating wound healing. Conclusion: This study provides broad prospects for the development of new hydrogel systems that can substantially improve the dynamic management of infected burn wounds.

Dual peptide-coordinated dynamic hydrogel with antibacterial and proangiogenic activities for infected skin wounds

Infected skin wounds represent a class of significant clinical challenges due to their complexity and the risk of delayed healing. Developing an effective wound dressing capable of promoting tissue regeneration while addressing infections is crucial. In this study, we designed a dual peptide-coordinated dynamic hydrogel with both antibacterial and proangiogenic properties, specifically tailored for treating infected skin wounds. The dynamic hydrogel was constructed using gelatin, a natural biomacromolecule with high biocompatibility, as the base material. Two functional peptides, the antibacterial melittin and angiogenic peptide, were incorporated to enhance both infection control and tissue repair. Hydrogelation was achieved through coordination interactions between gold (Au) ions and sulfhydryl groups, endowing the hydrogel with dynamic properties. The excellent biocompatibility, antibacterial efficacy and angiogenic capability of hydrogel allow it to provide structural support for wound healing while promoting cell proliferation and migration. By eradicating bacteria and stimulating new blood vessel formation, it accelerates the healing of infected wounds. Additionally, its injectability and self-healing properties make it suitable for treating irregularly shaped and deep wounds. This dual-functional hydrogel may offer a promising and minimally invasive treatment option for infected skin wounds, combining high biological safety with simplified surgical procedures.

Integrative multi-Omics and network pharmacology reveal angiogenesis promotion by Quan-Du-Zhong Capsule via VEGFA/PI3K-Akt pathway.

Quan-du-zhong capsule (QDZ), derived from the whole plant extract of Eucommiaulmoides Oliv., is a traditional Chinese herbal medicine used in treating vascular-related diseases, including hypertension and osteoporosis. Despite its established uses, its pro-angiogenic effects and underlying mechanisms require further investigation. This study aims to investigate the pro-angiogenic effects of QDZ and explore the underlying mechanisms. The chemical compositions of QDZ, including its absorbed prototypes in rats, were analyzed using UHPLC-Q Exactive-Orbitrap-MS. The pro-angiogenic activities of QDZ were evaluated in human umbilical vein endothelial cells (HUVECs) through various assays, including CCK-8, migration, scratch, tubule formation, and 3D sprouting assays. Additionally, the pro-angiogenic effects of QDZ were further assessed invivo through the matrigel plug assay and a hindlimb ischemia-reperfusion model, with three-dimensional blood flow visualized via micro-CT. A comprehensive approach involving network pharmacology, molecular docking, transcriptomics, and proteomics was utilized to explore the pro-angiogenic mechanism of QDZ, with validation by Western blot analysis. QDZ significantly promoted the proliferation, migration, and tubule formation of HUVECs. The matrigel plug assay further confirmed its pro-angiogenic potential. Invivo, QDZ-treated mice displayed enhanced vascular distribution and faster blood flow recovery post-ischemia-reperfusion. Chemical analysis identified 49 compounds in QDZ, with 16 absorbed prototypes detected in rat plasma. Mechanistic investigations through network pharmacology, transcriptomics, and proteomics suggested that QDZ's pro-angiogenic effects were mediated through the VEGFA/PI3K-Akt signaling pathway, with increased phosphorylation of angiogenesis-related proteins such as PI3K, Akt, FAK, and Src. This study demonstrates that QDZ promotes angiogenesis via activating the VEGFA and its downstream PI3K-Akt signaling pathway, shedding light on the mechanisms that underpin its traditional medicinal use in vascular health.

A New Methylbutyric Acid Derivative with Pro-angiogenesis Activity from the Mangrove Fungus Penicillium polonicum M-3.

A new methylbutyric acid derivative penianoic acid A (1), along with fifteen known compounds (2-16), was isolated and identified from the culture extract of Penicillium polonicum M-3 sourced from Malaysian mangrove root soil. Their structures were determined by detailed spectroscopic analysis of NMR and MS data and quantum chemical calculations of ECD and NMR (with DP4+ probability analysis). The isolated compounds were evaluated for pro-angiogenesis activity using zebrafish in vivo model. Compounds 1, 3, 4, 6-10, and 12-15 showed potent in pro-angiogenic activity in transgenic zebrafish.

Biphasic Calcium Phosphate Ceramic Scaffold Composed of Zinc Doped β-Tricalcium Phosphate and Silicon Doped Hydroxyapatite for Bone Tissue Engineering.

The rapid repair of bone defects remains a significant clinical challenge to this day. To address this issue, a 3D-printed biphasic calcium phosphate (BCP) scaffold consisting of 40 wt % hydroxyapatite (HA) and 60 wt % β-tricalcium phosphate (β-TCP) was created. Silicon and zinc were incorporated into HA and β-TCP, respectively, to enhance the angiogenic and osteogenic properties of the BCP scaffold. The physicochemical properties, in vitro cell responses, and bone defect repair efficacy of the modified BCP scaffold were comprehensively investigated. Results showed that the fabricated scaffold possessed a 3D interconnected pore structure. Zinc doping enhanced the sintering of the BCP scaffold, increased its density and strength, but decreased its degradation rate. Conversely, silicon doping had the opposite effect. The modified scaffold was capable of a gradual release of zinc/silicon ions, which promoted the proliferation and differentiation of cells. Specifically, the scaffold doped with zinc significantly promoted the osteogenic differentiation of stem cells. Moreover, co-doping with silicon and zinc synergistically promoted in vitro angiogenesis, with BCP-3 (doped with 2.5 mol % zinc and 4 mol % silicon) exhibiting the best pro-angiogenic activity. BCP-3 significantly induced regeneration of blood vessels and bone tissue in vivo, indicating its potential to accelerate the process of bone defect repair.

Dental pulp mesenchymal stem cell (DPSCs)-derived soluble factors, produced under hypoxic conditions, support angiogenesis via endothelial cell activation and generation of M2-like macrophages

BackgroundCell therapy has emerged as a revolutionary tool to repair damaged tissues by restoration of an adequate vasculature. Dental Pulp stem cells (DPSC), due to their easy biological access, ex vivo properties, and ability to support angiogenesis have been largely explored in regenerative medicine.MethodsHere, we tested the capability of Dental Pulp Stem Cell-Conditioned medium (DPSC-CM), produced in normoxic (DPSC-CM Normox) or hypoxic (DPSC-CM Hypox) conditions, to support angiogenesis via their soluble factors. CMs were characterized by a secretome protein array, then used for in vivo and in vitro experiments. In in vivo experiments, DPSC-CMs were associated to an Ultimatrix sponge and injected in nude mice. After excision, Ultimatrix were assayed by immunohistochemistry, electron microscopy and flow cytometry, to evaluate the presence of endothelial, stromal, and immune cells.For in vitro procedures, DPSC-CMs were used on human umbilical-vein endothelial cells (HUVECs), to test their effects on cell adhesion, migration, tube formation, and on their capability to recruit human CD14+ monocytes.ResultsWe found that DPSC-CM Hypox exert stronger pro-angiogenic activities, compared with DPSC-CM Normox, by increasing the frequency of CD31+ endothelial cells, the number of vessels and hemoglobin content in the Ultimatrix sponges. We observed that Utimatrix sponges associated with DPSC-CM Hypox or DPSC-CM Normox shared similar capability to recruit CD45− stromal cells, CD45+ leukocytes, F4/80+ macrophages, CD80+ M1-macrophages and CD206+ M2-macropages. We also observed that DPSC-CM Hypox and DPSC-CM Normox have similar capabilities to support HUVEC adhesion, migration, induction of a pro-angiogenic gene signature and the generation of capillary-like structures, together with the ability to recruit human CD14+ monocytes.ConclusionsOur results provide evidence that DPSCs-CM, produced under hypoxic conditions, can be proposed as a tool able to support angiogenesis via macrophage polarization, suggesting its use to overcome the issues and restrictions associated with the use of staminal cells.

Pan-Cancer Single-Cell Transcriptomic Analysis Reveals Divergent Expression of Embryonic Proangiogenesis Gene Modules in Tumorigenesis.

Angiogenesis is indispensable for the sustained survival and progression of both embryonic development and tumorigenesis. This intricate process is tightly regulated by a multitude of pro-angiogenic genes. The presence of gene modules facilitating angiogenesis has been substantiated in both embryonic development and the context of tumor proliferation. However, it remains unresolved whether the pro-angiogenic gene modules expressed during embryonic development also exist in tumors. This study performed a pan-cancer single-cell RNA sequencing (scRNA-seq) analysis on samples from 332 patients across seven cancer types: thyroid carcinoma, lung cancer, breast cancer, hepatocellular carcinoma, colorectal cancer, ovarian carcinoma, and prostate adenocarcinoma. Data processing was carried out using the Seurat R package, with rigorous quality control to filter high-quality cells and mitigate batch effects across datasets. We used principal component analysis (PCA), shared nearest neighbor graph-based clustering, and Uniform Manifold Approximation and Projection (UMAP) to visualize cell types and identify distinct cell clusters. Myeloid cell subpopulations were further analyzed for the expression of embryonic pro-angiogenic gene modules (EPGM) and tumor pro-angiogenic gene modules (TPGM). The analysis identified nine major cell types within the tumor microenvironment, with myeloid cells consistently exhibiting elevated expression of both tumor pro-angiogenic gene modules (TPGM) and EPGM across all tumor types. In particular, myeloid cells, including macrophages and monocytes, showed high EPGM expression, indicating an active role of embryonic pro-angiogenesis pathways in tumors. A subset analysis revealed 20 distinct myeloid subtypes with varying EPGM and TPGM expression across different cancers. Treatment and disease stage influenced these gene expressions, with certain subtypes, such as HSPAhi/STAT1+ macrophages in breast cancer, displaying reduced pro-angiogenic gene activity post-treatment. This study provides evidence that tumors may exploit EPGM to enhance vascularization and support sustained growth, as evidenced by the elevated EPGM expression in tumor-associated myeloid cells. The consistent presence of EPGM in TAMs across multiple cancer types suggests a conserved mechanism wherein tumors harness embryonic angiogenic pathways to facilitate their progression. Distinct EPGM expression patterns in specific myeloid cell subsets indicate potential therapeutic targets, particularly in cases where EPGM activation contributes to resistance against anti-angiogenic therapies. These findings shed new light on the molecular mechanisms underlying tumor angiogenesis and highlight the prognostic relevance of EPGM expression in cancer, underscoring its potential as a biomarker for clinical applications.

Co-inhibition of PGF and VEGFA enhances the effectiveness of immunotherapy in bladder cancer.

Background: Anti-angiogenic inhibitors and immune checkpoint blockade combination therapy offers a novel approach to circumvent the challenges associated with limited responsiveness to checkpoint inhibitors in bladder cancer. However, the effective strategies for inhibiting angiogenesis in bladder cancer need further elucidation. Objective: This work aims to identify key targets for the effective inhibition of angiogenesis in bladder cancer and to explore the potential benefits of combining anti-angiogenic therapies with immune checkpoint blockade strategies in the treatment of this disease. Methods: Cell-cell interaction analysis was performed using bladder cancer single-cell transcriptome datasets downloaded from the Gene Expression Omnibus (GEO) database to determine the regulatory network driving angiogenesis in bladder cancer. The bladder cancer cell line MBT2 was orthotopically transplanted into mice to investigate the impact of pro-angiogenic molecules on angiogenesis and tumor growth, and to evaluate the synergistic therapeutic potential of a combination therapy targeting angiogenesis and Programmed Cell Death Protein 1 (PD-1). Proliferation and tube formation assays with Human Umbilical Vein Endothelial Cells (HUVECs) were used to explore the regulatory functions of pro-angiogenic molecules in angiogenesis. Results: Placental growth factor (PGF) is a pro-angiogenic factor in bladder cancer, in addition to vascular endothelial growth factor A (VEGFA). Suppression of PGF reduced the tumor size and angiogenesis in bladder cancer. The expression level of vascular endothelial growth factor receptor 1 (VEGFR1) is higher than that of vascular endothelial growth factor receptor2 (VEGFR2) in the endothelial cells of bladder cancer. The pro-angiogenic activity of PGF is dependent on the expression level of VEGFR1 in endothelial cells. The combined inhibition of PGF and VEGFA exerts a synergistic effect on suppressing tumor growth and angiogenesis. The concurrent inhibition of PGF and VEGFA stands out as the only intervention capable of significantly enhancing the infiltration of CD8+ cytotoxic T cells within the bladder cancer microenvironment. In the bladder cancer mouse model, the introduction of an anti- programmed cell death protein 1 (PD-1) therapeutic regimen combined with the targeted inhibition of PGF and VEGFA, led to a significantly elevated survival rate compared to the outcome observed with anti-PD-1 monotherapy. Conclusion: PGF is a pro-angiogenic molecule in bladder cancer that requires significant expression levels of VEGFR1 in endothelial cells. Notably, the concurrent inhibition of PGF and VEGFA amplifies the therapeutic impact of anti-PD-1 treatment in bladder cancer. These findings provide further insights into the role of PGF in angiogenesis regulation and have conceptual implications for combining anti-angiogenic therapy with immune therapy in bladder cancer treatment.

Emerging innovative treatment strategies for advanced clear cell renal cell carcinoma.

Dramatic advances in biological discoveries, since the 1990s, have continued to reshape the treatment paradigm of metastatic renal cell carcinoma (RCC). Von Hippel Lindau (VHL) gene alterations are associated with pro-angiogenic activity and are central to the pathogenesis of clear cell RCC (ccRCC), the most predominant histologic subtype of RCC. Antiangiogenic strategies revolving around this VHL/HIF/VEGF axis have been shown to improve survival in metastatic ccRCC. The discovery of immune checkpoints and agents that target their inhibition introduced a new treatment paradigm for patients with RCC. While initially approved as monotherapy, studies investigating immune checkpoint inhibitor combinations have led to their approval as the new standard of care, providing durable responses and unprecedented improvements in clinical outcome. Despite these advances, the projected 14390 deaths in 2024 from RCC underscore the need to continue efforts in expanding and optimizing treatment options for patients with metastatic RCC. This article reviews key findings that have transformed the way we understand and treat metastatic RCC, in addition to highlighting novel treatment strategies that are currently under development.

CD74+ fibroblasts proliferate upon mechanical stretching to promote angiogenesis in keloids.

The healing of human skin wounds is susceptible to perturbation caused by excessive mechanical stretching, resulting in enlarged scars, hypertrophic scars, or even keloids in predisposed individuals. Keloids are fibro-proliferative scar tissues that extend beyond the initial wound boundary, consisting of the actively progressing periphery and the quiescent center. The stretch-associated outgrowth and enhanced angiogenesis are two features of the periphery of keloids. However, which cell population is responsible for transducing the mechanical stimulation to the progression of keloids remains unclear. Herein, through integrative analysis of single-cell RNA sequencing of keloids, we identified CD74+ fibroblasts, a previously unappreciated subset of fibroblasts with pro-angiogenic and stretch-induced proliferative capacities, as a key player in stretch-induced progression of keloids. Immunostaining of keloid cryosections depicted a predominant distribution of CD74+ fibroblasts in the periphery, interacting with the vasculature. Invitro tube formation assays on purified CD74+ fibroblasts ascertained their pro-angiogenic function. BrdU assays revealed that these cells proliferate upon stretching, through PIEZO1-mediated calcium influx and the downstream ERK and AKT signaling. Collectively, our findings propose a model wherein CD74+ fibroblasts serve as pivotal drivers of stretch-induced keloid progression, fueled by their proliferative and pro-angiogenic activities. Targeting the attributes of CD74+ fibroblasts holds promise as a therapeutic strategy for the management of keloids.

Evaluation of Local Injection of Adipose-Tissue Derived Stromal Vascular Fraction in Localized Scleroderma

Abstract Background Localized scleroderma (LoS) is a rare connective tissue disease affectig children and adults. It comprises a spectrum of sclerotic diseases that primarily affect the skin. Treatment of morphea is a challenge, several immunotherapies that specifically target cytokine or fibrosis signaling pathways, are under investigation and no treatment till now is considered gold standard. Among the most promising therapeutic approaches for fibrosing diseases are Adipose Stem Cells (ASCs). The scientific basis for studying ASCs treatment potential is their potent immunosuppressive, pro-angiogenic, and antifibrotic activities. Materials and Methods 20 patients suffering from morphea lesions were injected by ASCs locally. Follow up and assessment were done through validated clinical scoring, durometer measurement of skin hardness and histopathological measurements of dermal collagen thickness and density. Conclusion ASCs are promising therapeutic option and tool in addressing skin fibrosing diseases.

Single-cell characterization of differentiation trajectories and drug resistance features in gastric cancer with peritoneal metastasis.

Gastric cancer patients with peritoneal metastasis (GCPM) experience a rapidly deteriorating clinical trajectory characterized by therapeutic resistance and dismal survival, particularly following the development of malignant ascites. However, the intricate dynamics within the peritoneal microenvironment (PME) during the treatment process remain largely unknown. Matched samples from primary tumours (PT), peritoneal metastases (PM), and paired pre-treatment and post-chemo/immunotherapy (anti-PD-1/PD-L1) progression malignant ascites samples, were collected from 48 patients. These samples were subjected to single-cell RNA sequencing (n=30), multiplex immunofluorescence (n=30), and spatial transcriptomics (n=3). Furthermore, post hoc analyses of a phase 1 clinical trial (n=20, NCT03710265) and an in-house immunotherapy cohort (n=499) were conducted to validate the findings. Tracing the evolutionary trajectory of epithelial cells unveiled the terminally differentially MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential, and they demonstrated spatial proximity with fibroblasts and endothelial cells, correlating with poor prognosis. A significant expansion of macrophage infiltrates, which exhibited the highest proangiogenic activity, was observed in the ascites compared with PT and PM. Besides, higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates in therapeutic failure cases, potentially mediated by the LGALS9-CD45 and SPP1-CD44 ligand-receptor interactions. In the chemoresistant group, intimate interactions between C1Q+ macrophages and fibroblasts through the complement activation pathway were found. In the group demonstrating immunoresistance, heightened TGF-β production activity was detected in MUC1+ cancer cells, and they were skewed to interplay with C1Q+ macrophages through the GDF15-TGF-βR2 axis. Ultimately, post hoc analyses indicated that co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at the time of diagnosis. Our findings elucidated the cellular differentiation trajectories and crucial drug resistance features within PME, facilitating the exploration of effective targets for GCPM treatment. MUC1+ cancer cells with a high epithelial-to-mesenchymal transition potential and exhibiting spatial proximity to fibroblasts and endothelial cells constitute the driving force of gastric cancer peritoneal metastasis (GCPM). Higher C1Q+ macrophage infiltrates correlated with significantly lower GZMA+ T-lymphocyte infiltrates within the peritoneal microenvironment in therapeutic failure cases. Co-targeting TGF-β and PDL1 pathways may confer superior clinical benefits than sole anti-PD-1/PD-L1 therapy for patients presenting with GCPM at diagnosis.

Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis

ObjectivesVasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved.MethodsTranscriptomes and chromatin...

L-Arginine-Loaded Oxidized Isabgol/Chitosan-Based Biomimetic Composite Scaffold Accelerates Collagen Synthesis, Vascularization, and Re-epithelialization during Wound Healing in Diabetic Rats.

Impaired wound healing in diabetic wounds is common due to infection, inflammation, less collagen synthesis, and vascularization. Diabetic wound healing in patients is still a challenge and needs an ideal wound dressing to treat and manage diabetic wounds. Herein, an efficacious wound dressing biomaterial was fabricated by cross-linking oxidized isabgol (Oisab) and chitosan (Cs) via trisodium trimetaphosphate and Schiff base bonds. l-Arginine (l-Arg) was incorporated as a bioactive substance in the Oisab + Cs scaffold to promote cell adhesion, cell proliferation, collagen synthesis, and vascularization. The fabricated scaffolds showed microporous networks in the scanning electron microscopy analysis. The scaffold also possessed excellent hemocompatibility. In vitro studies using fibroblasts (L929 and human dermal fibroblast cells) confirmed the cytocompatibility of these scaffolds. The results of the in vivo chicken chorioallantoic membrane assay confirmed the proangiogenic activity of the Oisab + Cs + l-Arg scaffolds. The wound-healing potential of these scaffolds was studied in streptozotocin-induced diabetic rats. This in vivo study showed that the period of epithelialization in the Oisab + Cs + l-Arg scaffold-treated wounds was 21.67 ± 1.6 days, which was significantly faster than the control (30.33 ± 2.5 days). Histological and immunohistochemical studies showed that the Oisab + Cs + l-Arg scaffolds significantly accelerated the rate of wound contraction by reducing inflammation, improving collagen synthesis, and promoting neovascularization. These findings suggest that the Oisab + Cs + l-Arg scaffolds could be beneficial in treating diabetic wounds in clinical applications.

Enhancing bone repair through improved angiogenesis and osteogenesis using mesoporous silica nanoparticle-loaded Konjac glucomannan-based interpenetrating network scaffolds

We have fabricated and characterized novel bioactive nanocomposite interpenetrating polymer network (IPN) scaffolds to treat bone defects by loading mesoporous silica nanoparticles (MSNs) into blends of Konjac glucomannan, polyvinyl alcohol, and polycaprolactone. By loading MSNs, we developed a porous nanocomposite scaffold with mechanical strengths comparable to cancellous bone. In vitro cell culture studies proved the cytocompatibility of the nanocomposite scaffolds. RT-PCR studies confirmed that these scaffolds significantly upregulated major osteogenic markers. The in vivo chick chorioallantoic membrane (CAM) assay confirmed the proangiogenic activity of the nanocomposite IPN scaffolds. In vivo studies were performed using Wistar rats to evaluate the scaffolds' compatibility, osteogenic activity, and proangiogenic properties. Liver and renal function tests confirmed that these scaffolds were nontoxic. X-ray and μ-CT results show that the bone defects treated with the nanocomposite scaffolds healed at a much faster rate compared to the untreated control and those treated with IPN scaffolds. H&E and Masson's trichrome staining showed angiogenesis near the newly formed bone and the presence of early-stage connective tissues, fibroblasts, and osteoblasts in the defect region at 8 weeks after surgery. Hence, these advantageous physicochemical and biological properties confirm that the nanocomposite IPN scaffolds are ideal for treating bone defects.

GLP-1RA therapy increases circulating vascular regenerative cell content in people living with type 2 diabetes.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline-recommended therapies for the management of type 2 diabetes (T2D), atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease. We previously observed in people living with T2D and coronary artery disease that circulating vascular regenerative (VR) progenitor cell content increased following 6-mo use of the SGLT2 inhibitor empagliflozin. In this post hoc subanalysis of the ORIGINS-RCE CardioLink-13 study (ClinicalTrials.gov Identifier NCT05253521), we analyzed the circulating VR progenitor cell content of 92 individuals living with T2D, among whom 20 were on a GLP-1RA, 42 were on an SGLT2 inhibitor but not a GLP-1RA, and 30 were on neither of these vascular protective therapies. In the GLP-1RA group, the mean absolute count of circulating VR progenitor cells defined by high aldehyde dehydrogenase (ALDH) activity (ALDHhiSSClow) and VR progenitor cells further characterized by surface expression of the proangiogenic marker CD133 (ALDHhiSSClowCD133+) was higher than the group receiving neither a GLP-1RA nor an SGLT2 inhibitor (P = 0.02) and comparable with that in the SGLT2 inhibitor group (P = 0.25). The absolute count of proinflammatory, granulocyte-restricted precursor cells (ALDHhiSSChi) was significantly lower in the GLP-1RA group compared with the group on neither therapy (P = 0.031). Augmented vessel repair initiated by VR cells with previously documented proangiogenic activity, alongside a reduction in systemic, granulocyte precursor-driven inflammation, may represent novel mechanisms responsible for the cardiovascular-metabolic benefits of GLP-1RA therapy. Prospective, randomized clinical trials are now warranted to establish the value of recovering circulating VR progenitor cell content with blood vessel regenerative functions.NEW & NOTEWORTHY In this post hoc subanalysis of 92 individuals living with T2D and at high cardiovascular risk, the authors summarize the differences in circulating vascular regenerative (VR) progenitor cell content between those on GLP-1RA therapy, on SGLT2 inhibitor without GLP-1RA therapy, and on neither therapy. Those on GLP-1RA therapy demonstrated greater circulating VR progenitor cell content and reduced proinflammatory granulocyte precursor content. These results offer novel mechanistic insights into the cardiometabolic benefits associated with GLP-1RA therapy.

Pro-angiogenic effects of Guo Min decoction in a zebrafish model

ABSTRACT Objectives: Guo Min decoction (GMD) is a Chinese traditional medicine that can regulate allergy-related symptoms. Although GMD treatment was reported to treat allergy-associated symptoms by regulating the immune response, the rationale between GMD treatment and angiogenesis has not been reported yet. Our objective is to investigate the angiogenesis-modulating activity of GMD. Materials and Methods: In this study, we used fluorescence recording, alkaline phosphatase (AP) activity staining, and real-time polymerase chain reaction (PCR) experiments to examine the effects of GMD on angiogenesis in a zebrafish model. Results: GMD-treated zebrafish embryos exhibited more intercapillary spaces in the caudal vein plexus (Mock: 11.1 ± 1.8 [n = 20; n: numbers of embryos]; GMD-treated: 16.2 ± 1.9 [n = 20]). AP activity staining showed that treatment with GMD and liquorice (Gan Cao, a component of GMD) induced subintestinal vein outgrowth. However, glycyrrhizin (a component of Gan Cao) had no obvious pro-angiogenic effects on zebrafish. Furthermore, real-time PCR experiments indicated that GMD exposure might be through regulating angiogenesis-related genes (cdh5, nrp1a, and flt1) expressions. Conclusion: Based on these observations, we proposed that GMD had pro-angiogenic activity in a zebrafish model, and it might partially be contributed by one of the components, liquorice.

Comparative Study of Unfractionated Heparins and Low Molecular Weight Heparin on Skin Wound Repair

Aims: Heparin (HP) has aroused interest in the treatment of skin wounds. The HP extraction sources and the chemical diversity of its structural chain result in different clinical responses. In this study, a comparison was made among the effects of unfractionated heparin from bovine (bovHP) and swine (swi.HP) sources and low molecular weight heparin (LMWH) on skin lesions treatment. Study Design: Wounds were induced on the back of Swiss mice using a punch. Then, the wounds were treated with heparins for 3 and 7 days. Place and Duration of Study: Institute of Biomedical Sciences and Animal Breeding Network and Rodents of the Federal University of Uberlândia, between April 2018 and February 2020. Methodology: Wound closure was performed with a digital caliper. The inflammatory infiltrate was assessed by the activity of neutrophils and macrophages. Angiogenesis was measured by quantifying blood vessels and measuring hemoglobin. While fibrogenesis was assessed by picrosirius red staining. Results: None of the heparins had a healing effect. Swi.HP showed delay in wound closure and intensification of the inflammatory process compared to bov.HP. Swine and bovine heparins showed pro-angiogenic activity, although this did not differ between them. Difference between the groups of heparins was observed in relation to the deposition and organization of collagen fibers, with a reduction in fibrogenesis in wounds of the LMWH group compared to the other heparins, especially bov.HP. A better fibrogenic activity was observed for bov.HP. Conclusion: Thus, we conclude that the source of the heparin used should be considered, as its pharmacological response for wound treatment is quite diverse. Although none of the heparins was able to accelerate wound closure, bov.HP had an anti-inflammatory and pro- fibrogenic effect compared to the other heparins and therefore showed the best response in this experimental model.

Proangiogenic properties of complement protein C1q can contribute to endometriosis.

Endometriosis (EM) is defined as the engraftment and proliferation of functional endometrial-like tissue outside the uterine cavity, leading to a chronic inflammatory condition. While the precise etiology of EM remains elusive, recent studies have highlighted the crucial involvement of a dysregulated immune system. The complement system is one of the predominantly altered immune pathways in EM. Owing to its involvement in the process of angiogenesis, here, we have examined the possible role of the first recognition molecule of the complement classical pathway, C1q. C1q plays seminal roles in several physiological and pathological processes independent of complement activation, including tumor growth, placentation, wound healing, and angiogenesis. Gene expression analysis using the publicly available data revealed that C1q is expressed at higher levels in EM lesions compared to their healthy counterparts. Immunohistochemical analysis confirmed the presence of C1q protein, being localized around the blood vessels in the EM lesions. CD68+ macrophages are the likely producer of C1q in the EM lesions since cultured EM cells did not produce C1q in vitro. To explore the underlying reasons for increased C1q expression in EM, we focused on its established pro-angiogenic role. Employing various angiogenesis assays on primary endothelial endometriotic cells, such as migration, proliferation, and tube formation assays, we observed a robust proangiogenic effect induced by C1q on endothelial cells in the context of EM. C1q promoted angiogenesis in endothelial cells isolated from EM lesions (as well as healthy ovary that is also rich in C1q). Interestingly, endothelial cells from EM lesions seem to overexpress the receptor for the globular heads of C1q (gC1qR), a putative C1q receptor. Experiments with siRNA to silence gC1qR resulted in diminished capacity of C1q to perform its angiogenic functions, suggesting that C1q is likely to engage gC1qR in the pathophysiology of EM. gC1qR can be a potential therapeutic target in EM patients that will disrupt C1q-mediated proangiogenic activities in EM.

Prognostic value of circulatory growth factors to predict responsiveness to chemotherapy and remission status of patients with acute myeloid leukemia

IntroductionTumor neovascularization, an essential requirement for malignant disease progression and metastasis, depends on the dysregulation of pro-angiogenic and anti-angiogenic activities. This study aimed to investigate the utilization of circulatory angiopoietins (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF-A and VEGF-C), and basic fibroblast growth factor (bFGF) as a prognostic tool for acute myeloid leukemia (AML).Material and methodsTwenty-four AML patients who were under chemotherapeutic intervention were included. Patients’ relapse status, responsiveness to chemotherapy, and remission status were obtained from their medical profiles. For comparative purposes, fifteen healthy subjects were included. Serum levels of growth factors were measured.ResultsAs compared to control subjects, AML patients had significantly lower average levels of Ang-1 (170.8 ±12.7 versus 59.2 ±12.5 ng/ml) and VEGF-A (56.0 ±13.1 versus 98.6 ±11.9 ng/dl) that coincide with a higher average level of Ang-2 (18.5 ±4.1 ng/ml versus 7.5 ±0.8 ng/ml). Spearman’s correlation analysis defined a significant association of sAng-1 and sAng-2 with patients’ response to chemotherapy ( = 0.488) and remission status ( = 0.476), respectively. According to the receiver operating characteristic (ROC) curve, downregulation of Ang-1 has good predictivity for poor responsiveness to chemotherapy (AUC = 0.781, p < 0.05) while upregulation of sAng-2 has good predictivity for failed remission status (AUC = 0.779, p < 0.05).ConclusionsIn the context of AML, dysregulated circulatory levels of Ang-1 and Ang-2 are suggested prognostic markers to provide useful predictivity of patients’ adverse responsiveness to chemotherapy and remission status, respectively.