Expression Of Angiogenic Factors Research Articles

Collagen-Containing Fish Sidestream-Derived Protein Hydrolysates Support Skin Repair via Chemokine Induction.

Restoring homeostasis following tissue damage requires a dynamic and tightly orchestrated sequence of molecular and cellular events that ensure repair and healing. It is well established that nutrition directly affects skin homeostasis, while malnutrition causes impaired tissue healing. In this study, we utilized fish sidestream-derived protein hydrolysates including fish collagen as dietary supplements, and investigated their effect on the skin repair process using a murine model of cutaneous wound healing. We explored potential differences in wound closure and histological morphology between diet groups, and analyzed the expression and production of factors that participate in different stages of the repair process. Dietary supplementation with fish sidestream-derived collagen alone (Collagen), or in combination with a protein hydrolysate derived from salmon heads (HSH), resulted in accelerated healing. Chemical analysis of the tested extracts revealed that Collagen had the highest protein content and that HSH contained the great amount of zinc, known to support immune responses. Indeed, tissues from mice fed with collagen-containing supplements exhibited an increase in the expression levels of chemokines, important for the recruitment of immune cells into the damaged wound region. Moreover, expression of a potent angiogenic factor, vascular endothelial growth factor-A (VEGF-A), was elevated followed by enhanced collagen deposition. Our findings suggest that a 5%-supplemented diet with marine collagen-enriched supplements promotes tissue repair in the model of cutaneous wound healing, proposing a novel health-promoting use of fish sidestreams.

Adiponectin and Leptin Exert Antagonizing Effects on HUVEC Tube Formation and Migration Modulating the Expression of CXCL1, VEGF, MMP-2 and MMP-9.

Adiponectin and leptin are two abundant adipokines with different properties but both described such as potent factors regulating angiogenesis. AdipoRon is a small-molecule that, binding to AdipoRs receptors, acts as an adiponectin agonist. Here, we investigated the effects of AdipoRon and leptin on viability, migration and tube formation on a human in vitro model, the human umbilical vein endothelial cells (HUVEC) focusing on the expression of the main endothelial angiogenic factors: hypoxia-inducible factor 1-alpha (HIF-1α), C-X-C motif chemokine ligand 1 (CXCL1), vascular endothelial growth factor A (VEGF-A), matrix metallopeptidase 2 (MMP-2) and matrix metallopeptidase 9 (MMP-9). Treatments with VEGF-A were used as positive control. Our data revealed that, at 24 h treatment, proliferation of HUVEC endothelial cells was not influenced by AdipoRon or leptin administration; after 48 h longer exposure time, the viability was negatively influenced by AdipoRon while leptin treatment and the combination of AdipoRon+leptin produced no effects. In addition, AdipoRon induced a significant increase in complete tubular structures together with induction of cell migration while, on the contrary, leptin did not induce tube formation and inhibited cell migration; interestingly, the co-treatment with both AdipoRon and leptin determined a significant decrease of the tubular structures and cell migration indicating that leptin antagonizes AdipoRon effects. Finally, we found that the effects induced by AdipoRon administration are accompanied by an increase in the expression of CXCL1, VEGF-A, MMP-2 and MMP-9. In conclusion, our data sustain the active role of adiponectin and leptin in linking adipose tissue with the vascular endothelium encouraging the further deepening of the role of adipokines in new vessel’s formation, to candidate them as therapeutic targets.

CircSTK40 contributes to recurrent implantation failure via modulating the HSP90/AKT/FOXO1 axis

Increasing evidence has revealed a close relationship between non-coding RNAs and recurrent implantation failure (RIF). However, the role of circular RNAs (circRNAs) in RIF pathogenesis remains largely unknown. Microarray analyses were used to identify the differentially expressed circRNA-circSTK40. Functional experiments, including decidualization induction and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, were performed to determine the effects of circSTK40 on human endometrial stromal cells (ESCs). The interactions between circSTK40 and proteins were investigated by RNA pull-down, RNA immunoprecipitation, and co-immunoprecipitation (coIP) assays. We observed that circSTK40 expression was upregulated in the RIF midluteal-phase endometrial samples. circSTK40 overexpression in ESCs inhibited the decidualization process but concurrently enhanced cell survival during stress. Mechanistically, circSTK40 directly bound to HSP90 and CLU, thus functioning as a scaffold to block their interactions and hinder the proteasomal degradation of HSP90. The resulting high levels of HSP90 led to the activation of the AKT pathway and downregulation of FOXO1 expression. Inhibitors of AKT (MK-2206) and HSP90 (17AAG) both abolished the effects of circSTK40 overexpression in ESCs and increased the decidualization levels in a dose-dependent manner. Our findings indicate a novel epigenetic mechanism for RIF pathogenesis involving circSTK40 activity and provide a foundation for targeted treatments in patients with low endometrial receptivity.

Hyperoxia-induced S1P1 signaling reduced angiogenesis by suppression of TIE-2 leading to experimental bronchopulmonary dysplasia.

We have earlier shown that hyperoxia (HO)-induced sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling contribute to bronchopulmonary dysplasia (BPD). S1P acts through G protein-coupled receptors, S1P1 through S1P5. Further, we noted that heterozygous deletion of S1pr1 ameliorated the HO-induced BPD in the murine model. The mechanism by which S1P1 signaling contributes to HO-induced BPD was explored. S1pr1+/+ and S1pr1+/- mice pups were exposed to either room air (RA) or HO (75% oxygen) for 7 days from PN 1-7. Lung injury and alveolar simplification was evaluated. Lung protein expression was determined by Western blotting and immunohistochemistry (IHC). In vitro experiments were performed using human lung microvascular endothelial cells (HLMVECs) with S1P1 inhibitor, NIBR0213 to interrogate the S1P1 signaling pathway. HO increased the expression of S1pr1 gene as well as S1P1 protein in both neonatal lungs and HLMVECs. The S1pr1+/- neonatal mice showed significant protection against HO-induced BPD which was accompanied by reduced inflammation markers in the bronchoalveolar lavage fluid. HO-induced reduction in ANG-1, TIE-2, and VEGF was rescued in S1pr1+/- mouse, accompanied by an improvement in the number of arterioles in the lung. HLMVECs exposed to HO increased the expression of KLF-2 accompanied by reduced expression of TIE-2, which was reversed with S1P1 inhibition. HO induces S1P1 followed by reduced expression of angiogenic factors. Reduction of S1P1 signaling restores ANG-1/ TIE-2 signaling leading to improved angiogenesis and alveolarization thus protecting against HO-induced neonatal lung injury.

VEGF Regulation of Angiogenic Factors via Inflammatory Signaling in Myeloproliferative Neoplasms

Background: Chronic inflammation has been recognized in neoplastic disorders, including myeloproliferative neoplasm (MPN), as an important regulator of angiogenesis. Aims: We investigated the influence of vascular endothelial growth factor (VEGF) and pro-inflammatory interleukin-6 (IL-6) on the expression of angiogenic factors, as well as inflammation-related signaling in mononuclear cells (MNC) of patients with MPN and JAK2V617F positive human erythroleukemic (HEL) cells. Results: We found that IL-6 did not change the expression of angiogenic factors in the MNC of patients with MPN and HEL cells. However, IL-6 and the JAK1/2 inhibitor Ruxolitinib significantly increased angiogenic factors—endothelial nitric oxide synthase (eNOS), VEGF, and hypoxia-inducible factor-1 alpha (HIF-1α)—in patients with polycythemia vera (PV). Furthermore, VEGF significantly increased the expression of HIF-1α and eNOS genes, the latter inversely regulated by PI3K and mTOR signaling in the MNC of primary myelofibrosis (PMF). VEGF and inhibitors of inflammatory JAK1/2, PI3K, and mTOR signaling reduced the eNOS protein expression in HEL cells. VEGF also decreased the expression of eNOS and HIF-1α proteins in the MNC of PMF. In contrast, VEGF increased eNOS and HIF-1α protein expression in the MNC of patients with PV, which was mediated by the inflammatory signaling. VEGF increased the level of IL-6 immunopositive MNC of MPN. In summary, VEGF conversely regulated gene and protein expression of angiogenic factors in the MNC of PMF, while VEGF increased angiogenic factor expression in PV mediated by the inflammation-related signaling. Conclusion: The angiogenic VEGF induction of IL-6 supports chronic inflammation that, through positive feedback, further promotes angiogenesis with concomitant JAK1/2 inhibition.

CD44 Sorted Cells Have an Augmented Potential for Proliferation, Epithelial-Mesenchymal Transition, Stemness, and a Predominantly Inflammatory Cytokine and Angiogenic Secretome

Cancer stem cells (CSCs) have garnered attention with their potential for early diagnosis and prognosis of oral squamous cell carcinoma (OSCC). It is still indistinct whether CSCs are recognized with a specific set of characteristics. The present study aimed to assess the association of CD44 with stemness-related, Epithelial Mesenchymal Transition EMT-related genes and the secretome of the CSCs. The single-cell suspension from primary OSCC tumors was prepared by enzymatic digestion and the cells were cultured in-vitro. The cancer stem cells were isolated by CD44+ selection using magnetic cell-sorting. The expression of CD44, proliferation rate, gene expression of EMT-related transcription factors, stemness markers, cytokine levels and angiogenic factors in both cell population was assessed. The sorted CD44+ cells showed significantly higher proliferation rate than heterogenous population. The CD44 expression was >90% in the sorted cells which was higher than the heterogenous cells. The CD44+ CSCs cells demonstrated significant increased levels of EMT-related genes TWIST1 and CDH2 (N-cadherin), CSC-related genes CD44 and CD133 (PROM1), stemness-related genes OCT4, SOX2, inflammatory cytokines IL-1ß, IL-12, IL-18 and TNF-α and angiogenic factors Angiopoietin-1, Angiopoietin-2, bFGF and VEGF while levels of epithelial gene CDH1 (E-cadherin) decreased in comparison to mixed cell population. The genetic and secretome profiling of the CD44+ CSCs could serve as diagnostic and prognostic tools in the treatment of oral cancers.

Effects of exercise training with weight loss on skeletal muscle expression of angiogenic factors in overweight and obese older men.

Low skeletal muscle capillarization is associated with impaired glucose tolerance (IGT); however, aerobic exercise training with weight loss (AEX + WL) increases skeletal muscle capillarization and improves glucose tolerance in adults with IGT. Given that the expression of angiogenic growth factors mediates skeletal muscle capillarization, we sought to determine whether angiogenic growth factor levels are associated with low capillarization in those with IGT versus normal glucose tolerance (NGT) or to the benefits of AEX + WL in both groups. Sixteen overweight or obese men 50-75 yr of age completed 6 mo of AEX + WL with oral glucose tolerance tests and vastus lateralis muscle biopsies for measurement of muscle vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and basic fibroblast growth factor (bFGF). At baseline, all growth factor levels were numerically lower in IGT than NGT, but these did not reach statistical significance (P = 0.06-0.33). Following AEX + WL, aerobic capacity [maximal oxygen consumption (V̇o2max)] increased by 16%, whereas body weight and 120-min postprandial glucose levels decreased by 10% and 15%, respectively (P ≤ 0.001 for all). There was a main effect of AEX + WL to increase VEGF (0.095 ± 0.016 vs. 0.114 ± 0.018 ng/µg, P < 0.05), PlGF (0.004 ± 0.001 vs. 0.005 ± 0.001 ng/µg, P < 0.05), and sFlt-1 (0.216 ± 0.029 vs. 0.264 ± 0.036 ng/µg, P < 0.01), with overall increases driven by the IGT group. These results suggest that 6 mo of AEX + WL increases skeletal muscle angiogenic growth factor levels in obese older adults with IGT and NGT, which may contribute to our previous findings that AEX + WL increases capillarization to improve glucose tolerance in those with IGT.NEW & NOTEWORTHY Skeletal muscle capillarization is lower in adults with impaired glucose tolerance than normal controls. This may, in part, be attributable to differential expression of angiogenic growth factors in skeletal muscle. Using a 6-mo aerobic exercise intervention with ∼10% body weight loss (AEX + WL), we show that the expression of angiogenic growth factors tends to be lower in adults with impaired glucose tolerance compared with normal controls and that AEX + WL increased expression of angiogenic growth factors in all participants.

Dickkopf-1 perpetuated synovial fibroblast activation and synovial angiogenesis in rheumatoid arthritis.

Dickkopf-1 (Dkk-1), a regulatory molecule of the Wnt pathway, is elevated and leads to bone resorption in patients with RA. This study is aimed to investigate the contribution of Dkk-1 to synovial inflammation and synovial fibroblast-mediated angiogenesis in RA. The expression of Dkk-1 in RA synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF) was detected by real-time PCR and ELISA, respectively. RASF were stimulated with different pro-inflammatory factors. The expression of angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was analyzed by real-time PCR when Dkk-1 was inhibited or overexpressed. Meanwhile, the concentrations of MCP-1, IL-6, IL-8, and MMP-3 in the cell culture supernatant were assessed by ELISA. The effects of Dkk-1 on the MAPK signaling pathway were evaluated by western blot. Matrigel tube formation assay was employed to reveal the direct and indirect effects of Dkk-1 on synovial angiogenesis. Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression in RASF. The production of potent angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was elevated, whereas the reverse results were found in the inhibitor groups. Silenced Dkk-1expression in RASF dampened capillary tube organization in both direct and indirect manners, resulting in restrained ERK, JNK, and p38 signaling pathway activation. We concluded that Dkk-1 exacerbated the inflammation, cartilage erosion, and angiogenesis mediated by synovial fibroblasts in RA. Modulation of DKK-1 expression may facilitate development of novel strategies to control RA. Key points • Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. • Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression. • Silenced Dkk-1expression in RASF dampened capillary tube organization.

Serum-Derived Small Extracellular Vesicles From Diabetic Mice Impair Angiogenic Property of Microvascular Endothelial Cells: Role of EZH2.

BackgroundImpaired angiogenic abilities of the microvascular endothelial cell (MVEC) play a crucial role in diabetes mellitus–impaired ischemic tissue repair. However, the underlying mechanisms of diabetes mellitus–impaired MVEC function remain unclear. We studied the role of serum‐derived small extracellular vesicles (ssEVs) in diabetes mellitus–impaired MVEC function.Methods and ResultsssEVs were isolated from 8‐week‐old male db/db and db/+ mice by ultracentrifugation and size/number were determined by the Nano‐sight tracking system. Diabetic ssEVs significantly impaired tube formation and migration abilities of human MVECs. Furthermore, local transplantation of diabetic ssEVs strikingly reduced blood perfusion and capillary/arteriole density in ischemic hind limb of wildtype C57BL/6J mice. Diabetic ssEVs decreased secretion/expression of several pro‐angiogenic factors in human MVECs. Mechanistically, expression of enhancer of zest homolog 2 (EZH2), the major methyltransferase responsible for catalyzing H3K27me3 (a transcription repressive maker), and H3K27me3 was increased in MVECs from db/db mice. Diabetic ssEVs increased EZH2 and H3K27me3 expression/activity in human MVECs. Expression of EZH2 mRNA was increased in diabetic ssEVs. EZH2‐specific inhibitor significantly reversed diabetic ssEVs‐enhanced expression of EZH2 and H3K27me3, impaired expression of angiogenic factors, and improved blood perfusion and vessel density in ischemic hind limb of C57BL/6J mice. Finally, EZH2 inactivation repressed diabetic ssEVs‐induced H3K27me3 expression at promoter of pro‐angiogenic genes.ConclusionsDiabetic ssEVs impair the angiogenic property of MVECs via, at least partially, transferring EZH2 mRNA to MVECs, thus inducing the epigenetic mechanism involving EZH2‐enhanced expression of H3K27me3 and consequent silencing of pro‐angiogenic genes. Our findings unravel the cellular mechanism and expand the scope of bloodborne substances that impair MVEC function in diabetes mellitus.

Acetone Extract of Cornus officinalis Leaves Exerts Anti-Melanoma Effects via Inhibiting STAT3 Signaling.

PurposeThis research aims to investigate the intervention and mechanism of 50% acetone extract of C. officinalis leaves (SZYY) on melanoma xenografts.Patients and MethodsTumor size and cardiac function were measured via ultrasound. The accumulation of 2-deoxy-D-glucose (2-DG) in tumor tissue was examined with near-infrared in vivo imaging. Flow cytometry was performed to assess apoptosis and reactive oxygen species (ROS) levels in tumor and immune cells in spleen. The levels of inflammatory cytokines in serum were detected by cytometric bead array. The expression of proliferation-, apoptosis-, and angiogenesis-related proteins in tumor cells was measured to evaluate the underlying mechanisms. Subsequently, the effects of four compounds separated from SZYY on the proliferation and migration of A375 cells and STAT3 signaling were examined. The peak identification and contents of the four components were performed via high-performance liquid chromatography (HPLC). Finally, we evaluated the inhibitory effects of STAT3 overexpression on the cytotoxic activity of four constituents in A375 cells.ResultsSZYY inhibited the growth and glycolysis of melanoma xenograft in mice, improved cardiac function, increased the percentages of macrophages, neutrophils, and lymphocytes in spleen, reduced the levels of IL-6, IL-17A, TNF-α, and IFN-γ in serum, promoted apoptosis and oxidative stress in tumor tissues, and inhibited STAT3 phosphorylation and expression of angiogenic factors. Chemical analysis showed that SZYY is rich in loganin, rutin, triohimas C, and triohimas D, which all could restrain the proliferation and migration of A375 cells and inhibit the phosphorylation and nuclear translocation of STAT3. Moreover, STAT3 overexpression could diminish the cytotoxic activity of four compounds on A375 cells.ConclusionSZYY could exert anti-melanoma effects via inhibiting STAT3 signaling to induce apoptosis and inhibit tumor angiogenesis. Its active ingredients might be loganin, rutin, triohimas C, and triohimas D.

Decidualization modulates the mesenchymal stromal/stem cell and pericyte characteristics of human decidual stromal cells. Effects on antigen expression, chemotactic activity on monocytes and antitumoral activity

Decidual stromal cells (DSCs) are the most abundant cellular component of human decidua and play a central role in maternal–fetal immune tolerance. Antigen phenotyping and functional studies recently confirmed the relationship of DSCs with mesenchymal stem/stromal cells (MSCs) and pericytes, the latter two cell types being closely related or identical. The present study investigated the effect of decidualization, a process of cell differentiation driven by progesterone (P4) and other pregnancy hormones, on the MSC/pericyte characteristics of DSCs. To this end we isolated undifferentiated DSC (preDSC) lines that were decidualized in vitro (dDSC) by the effect of P4 and cAMP. Using flow cytometry, we found significant downmodulation of the expression of the MSC/pericyte markers α-smooth muscle actin, nestin, CD140b, CD146 and SUSD2 in dDSCs. The dDSCs did not differ, compared to preDSCs, in the expression of angiogenic factors (characteristic of pericytes) HGF, FGF2, ANGPT1 or VEGF according to RT-PCR results, but had significantly increased PGF expression. In migration assays, preDSC-conditioned media had a chemotactic effect on the THP-1 monocytic line (characteristic of pericytes), and this effect was significantly greater in dDSC-conditioned media. Media conditioned with dDSC, but not with preDSC, induced apoptosis in 4 out of 6 different tumor cell lines (characteristic of MSCs) according to propidium iodide staining and flow cytometry results. Our findings show that decidualization induces phenotypic and functional changes in the MSC/pericyte properties of DSCs that may have a role in the normal development of pregnancy.

BMI1 regulates multiple myeloma-associated macrophage\u2019s pro-myeloma functions

Multiple myeloma (MM) is an aggressive malignancy characterized by terminally differentiated plasma cells accumulation in the bone marrow (BM). MM BM exhibits elevated MΦs (macrophages) numbers relative to healthy BM. Current evidence indicates that MM-MΦs (MM-associated macrophages) have pro-myeloma functions, and BM MM-MΦs numbers negatively correlate with patient survival. Here, we found that BMI1, a polycomb-group protein, modulates the pro-myeloma functions of MM-MΦs, which expressed higher BMI1 levels relative to normal MΦs. In the MM tumor microenvironment, hedgehog signaling in MΦs was activated by MM-derived sonic hedgehog, and BMI1 transcription subsequently activated by c-Myc. Relative to wild-type MM-MΦs, BMI1-KO (BMI1 knockout) MM-MΦs from BM cells of BMI1-KO mice exhibited reduced proliferation and suppressed expression of angiogenic factors. Additionally, BMI1-KO MM-MΦs lost their ability to protect MM cells from chemotherapy-induced cell death. In vivo analysis showed that relative to wild-type MM-MΦs, BMI1-KO MM-MΦs lost their pro-myeloma effects. Together, our data show that BMI1 mediates the pro-myeloma functions of MM-MΦs.

Microconvex Dot-Featured Silk Fibroin Films for Promoting Human Umbilical Vein Endothelial Cell Angiogenesis via Enhancing the Expression of bFGF and VEGF.

Insufficient vascularization of grafts often leads to delayed tissue ingrowth and impaired tissue function in tissue engineering. The surface topography of grafts plays critical roles in angiogenesis. In the present study, we prepared silk fibroin (SF)-based microtopography films with the number of convex dots ranging from 37 to 4835/mm2. The convex dot-featured topography surfaces were characterized by scanning electron microscopy, a Profilm3D optical profilometer, atomic force microscopy, and a contact angle goniometer. The effect of microtopographic films on the proliferation, adhesion, and expression of angiogenic factors of human umbilical vein endothelial cells (HUVECs) was investigated. Our results demonstrated that the SF film surface with 2899 convex dots/mm2 significantly enhanced adhesion, viability, and levels of vascular endothelial growth factors and basic fibroblast growth factors of HUVECs and significantly downregulated the level of α-SMA in human aortic smooth muscle cells, indicating that the microtopographic films could promote angiogenesis. Furthermore, in vitro results showed that HUVEC proliferation was positively correlated with yes-associated protein (YAP) activation, suggesting that the enhanced angiogenesis was mediated via the YAP pathway. Finally, mice subcutaneous embedding model results indicated that the SF film surface with 2899 convex dots/mm2 could significantly enhance angiogenesis in vivo. Altogether, our results showed that the SF film surface with 2899 convex dots/mm2 promoted the angiogenesis of HUVECs and offered a novel angiogenesis-promoting strategy of implant surface design for tissue engineering.

Interactive effect of 6 weeks of High-intensity interval training and quercetin supplementation on expression of some tumor angiogenesis markers in female mice with breast cancer

Background: About angiogenesis, metastasis of breast cancer and exercise, Many studies have been done in recent decades to better understand of regulatory mechanisms. The purpose of this study was to investigate the Interactive effect of high-intensity interval training (HIIT) and quercetin supplementation (Q) on the expression of key angiogenic factors in tumor tissue of mouse with breast cancer. Methods: Twenty-four female Balb/C mouse were injected with estrogen receptor-dependent breast cancer cells MC4L2 and then divided into three groups of tumor (T), tumor + of high-intensity interval training (TH) and tumor + high-intensity interval training + quercetin (THQ). The TH and THQ groups ran the treadmill 3 days a week for 6 weeks and each session 1 hour. The THQ group received 110 mg / kg quercetin solution for 6 weeks, 3 days a week with training. After completion of the work, the mouse were sacrificed and their tumor tissue removed and frozen in liquid nitrogen And stored at -70 ° C. Expression of TIE-2 and VEGF-A genes was measured by REAL TIME-PCR. ΔCt, ΔΔCt, and Fold change were calculated with the relevant statistical tests at the significant level (P &lt;0.05) by GENEX software. Results: The results showed that THQ interaction significantly decreased the expression of TIE-2 and VEGF-A genes in TH and THQ groups compared to T group. In addition, quercetin in THQ group significantly decreased TIE-2 and VEGF-A gene expression compared to TH group. Conclusion: interaction of HIIT and Q supplementation are probably effective in inhibiting tumor angiogenesis.

Europium Hydroxide Nanorods Mitigate Hind Limb Ischemia in Wistar Rats

AbstractLack of adequate blood supply to the limb extremities results in critical limb ischemia (CLI) and subsequent tissue death. Conventional approaches for CLI treatment include bypass surgery and angioplasty, which achieved limited clinical success due to their complex invasiveness. Of late, growth factor and cell‐based therapies emerged as alternative treatment strategies for CLI. However, these strategies could not achieve much success due to the associated drawbacks. Earlier, this study group develops europium hydroxide nanorods (EHN) which demonstrates potential proangiogenic (stimulating new blood vessel growth) properties. Recently it is shown that EHN could ameliorate the myocardial ischemia in Wistar rats by promoting therapeutic angiogenesis and mitigate cadmium‐induced vascular toxicity. Considering the importance of revascularization in managing CLI, it is hypothesized that the proangiogenic EHN might be useful for its effective treatment. Hence, in the present study, the therapeutic efficacy of EHN is comprehensively evaluated in the hind limb ischemia model of Wistar rats. The EHN‐administered ischemic rats exhibit improved motility, enhanced blood flow to the ischemic limb along with increased expression of angiogenic factors. Additionally, toxicity and pharmacokinetic studies of EHN in mice demonstrate their nontoxic nature, suggesting the feasibility of their practical clinical application for CLI treatment.

Could the photobiomodulation therapy induce angiogenic growth factors expression from dental pulp cells?

This study aimed to evaluate the effect of different photobiomodulation (PBM) radiant exposures on the viability, proliferation, and gene expression of pulp fibroblasts from human primary teeth (HPF) involved in the pulp tissue repair. HPF were irradiated with Laser InGaAlP (Twin Flex Evolution, MMOptics®) at 660-nm wavelength (red); single time, continuous mode, 0.04-cm2 laser tip area, and 0.225-cm laser tip diameter, keeping the distance of 1 mm between the laser beam and the cell culture. The doses used were between 1.2 and 6.2 J/cm2 and were evaluated at the 6 h, 12 h, and 24 h after PBM. MTT and crystal violet assays evaluated the cell viability and proliferation. RT-PCR verified VEGF and FGF-2 mRNA expression. A blinded examiner analyzed the data through two-way ANOVA followed by Tukey test (p < 0.05). The groups with higher powers (10 mW, 15 mW, 20 mW, and 25 mW), shortest application periods (10 s), and radiant exposures between 2.5 and 6.2 J/cm2 exhibited statistically higher viability than that of the groups with small power (5 mW), longer application period (50 s), and radiant exposure of 6.2 J/cm2 (p < 0.05). VEGF and FGF-2 mRNA expression were observed at the three evaluated periods (6 h, 12 h, and 24 h) and the highest expression was in the shortest period (p < 0.05). All radiant exposures maintained HPF viable. The period of 6 h after irradiation showed statistically greater gene expression for both growth factors than other periods. VEGF mRNA had no differences among the dosimetries studied. The best radiant exposures for FGF-2 gene expression were 2.5 J/cm2 and 3.7 J/cm2.

A narrative review of research progress on the relationship between hypoxia-inducible factor-2α and wound angiogenesis.

This article aims to pay attention to the latest research on the expression, activation and function of hypoxia-inducible factor-2α (HIF-2α) under hypoxia and non-hypoxia conditions, and summarizes the current knowledge about the interaction between hypoxia-inducible factor-2 and angiogenesis, hoping to understand its actions in physiology and disease, with the goal of providing a new strategy for the diagnosis and treatment of wounds. Wound healing is a complex and continuous process, involving coagulation, inflammation, angiogenesis, new tissue formation and extracellular matrix remodeling. Of these, angiogenesis is an essential step. One of the main reasons for non-healing or delayed healing of wounds in peripheral vascular diseases and diabetes is the reduced ability to regenerate microvessels through the process of angiogenesis, which has become the focus of new methods for treating chronic wounds. HIF-2α regulates many aspects of angiogenesis, including vascular maturation, cell migration, proliferation and metastasis. Throughout extensive search of PubMed, summarize the medical research on HIF-2α to 2020. HIF-2α is necessary for normal embryonic development by stimulating the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF). It is essential for the formation of new blood vessels in physiological and pathophysiological environments. Targeting HIF-2α in wound healing has much clinical significance for tissue repair.

Roxadustat attenuates hyperoxia-induced lung injury by upregulating proangiogenic factors in newborn mice

Premature infants who require oxygen therapy for respiratory distress syndrome often develop bronchopulmonary dysplasia, a chronic lung disease characterized by interrupted alveologenesis. Disrupted angiogenesis inhibits alveologenesis; however, the mechanisms through which disrupted angiogenesis affects lung development are poorly understood. Hypoxia-inducible factors (HIFs) are transcription factors that activate multiple oxygen-sensitive genes, including those encoding for vascular endothelial growth factor (VEGF). However, the HIF modulation of angiogenesis in hyperoxia-induced lung injury is not fully understood. Therefore, we explored the effects of roxadustat, an HIF stabilizer that has been shown to promote angiogenesis, in regulating pulmonary angiogenesis on hyperoxia exposure. C57BL6 mice pups reared in room air and 85% O2 were injected with phosphate-buffered saline or 5mg/kg or 10mg/kg roxadustat. Their daily body weight and survival rate were recorded. Their lungs were excised for histology and angiogenic factor expression analyses on postnatal Day 7. Exposure to neonatal hyperoxia reduced body weight; survival rate; and expressions of von Willebrand factor, HIF-1α, phosphor mammalian target of rapamycin, VEGF, and endothelial nitric oxide synthase and increased the mean linear intercept values in the pups. Roxadustat administration reversed these effects. Hyperoxia suppressed pulmonary vascular development and the expression of proangiogenic factors. Roxadustat promoted pulmonary angiogenesis on hyperoxia exposure by stabilizing HIF-1α and upregulating the expression of proangiogenic factors, indicating its potential in clinical and therapeutic applications.

One zwitterionic injectable hydrogel with ion conductivity enables efficient restoration of cardiac function after myocardial infarction

An injectable zwitterionic polymer with an intrinsic ionic conductivity prepared from Michael addition reaction between acrylate-modified carboxybetaine macromonomer and DTT demonstrates an anti-oxidant/anti-inflammatory, vascularization-promoting activity. The betaine can down-regulate homocysteine level and its ever under-exploited conductivity is harnessed to facilitate transmission of electrical signal. • A polyzwitterion hydrogel is prepared via in situ Michael addition reaction. • This hydrogel is capable of promoting angiogenesis and suppressing fibrosis. • The conductivity of polyzwitterion is explored to treat MI for the first time. Conventional strategies for constructing an injectable conductive hydrogel for treatment of myocardial infarction (MI) are mostly involved with complicated bioactive modification and incorporation of external conductive materials or cells/therapeutic drugs, severely restraining its medical translation. Herein, a cell-free and therapeutic drug-free injectable zwitterionic hydrogel is fabricated by thiol-acrylate Michael addition reaction between acrylate modified polycarboxybetaine macromonomer and dithiothreitol (DTT), where the free DTT and the tethered-DTT endow the hydrogel with an antioxidant ability. The zwitterionic hydrogel is optimized to exhibit an appropriate gelation time and injectability. Intriguingly, the cation-anion ion pair on the side chain affords an intrinsic conductive property similar to the native myocardium. After injection into the infarcted region of rats, the hydrogel can downregulate level of inflammatory factors, and upregulate the expressions of cardiac-related factors, angiogenic factors, and transmission electrical signal-relevant Cx-43, accompanied by suppression of oxidant stress and cardiac fibrosis and increased vessel density, supposedly due to inherent antifouling, vascularization-promoting and conductive properties. Echocardiography and histological analyses demonstrate a remarkable improvement of the functions and structure of infarcted myocardium in rats in terms of 2.17/2.80-fold increase in ejection fraction/fractional shortening, 3.62-fold decline in end-systolic volume, and 2.39-fold decrease in fibrosis area, compared to MI group. This cell-free and therapeutic drug-free injectable zwitterionic hydrogel represents a new approach to seek a simplified but holistic biomaterial for treating myocardial infarction.

MAPKAP Kinase-2 Drives Expression of Angiogenic Factors by Tumor-Associated Macrophages in a Model of Inflammation-Induced Colon Cancer.

Chronic inflammation increases the risk for colorectal cancer through a variety of mechanisms involving the tumor microenvironment. MAPK-activated protein kinase 2 (MK2), a major effector of the p38 MAPK stress and DNA damage response signaling pathway, and a critical regulator of pro-inflammatory cytokine production, has been identified as a key contributor to colon tumorigenesis under conditions of chronic inflammation. We have previously described how genetic inactivation of MK2 in an inflammatory model of colon cancer results in delayed tumor progression, decreased tumor angiogenesis, and impaired macrophage differentiation into a pro-tumorigenic M2-like state. The molecular mechanism responsible for the impaired angiogenesis and tumor progression, however, has remained contentious and poorly defined. Here, using RNA expression analysis, assays of angiogenesis factors, genetic models, in vivo macrophage depletion and reconstitution of macrophage MK2 function using adoptive cell transfer, we demonstrate that MK2 activity in macrophages is necessary and sufficient for tumor angiogenesis during inflammation-induced cancer progression. We identify a critical and previously unappreciated role for MK2-dependent regulation of the well-known pro-angiogenesis factor CXCL-12/SDF-1 secreted by tumor associated-macrophages, in addition to MK2-dependent regulation of Serpin-E1/PAI-1 by several cell types within the tumor microenvironment.