Endogenous Vascular Endothelial Growth Factor Research Articles

Hemodynamic force dictates endothelial angiogenesis through MIEN1-ERK/MAPK-signaling axis.

It is well-recognized that blood flow at branches and bends of arteries generates disturbed shear stress, which plays a crucial in driving atherosclerosis. Flow-generated fluid shear stress (FSS), as one of the key hemodynamic factors, is appreciated for its critical involvement in regulating angiogenesis to facilitate wound healing and tissue repair. Endothelial cells can directly sense FSS but the mechanobiological mechanism by which they decode different patterns of FSS to trigger angiogenesis remains unclear. In the current study, laminar shear stress (LSS, 15 dyn/cm2) was employed to mimic physiological blood flow, while disturbed shear stress (DSS, ranging from 0.5 ± 4 dyn/cm2) was applied to simulate pathological conditions. The aim was to investigate how these distinct types of blood flow regulated endothelial angiogenesis. Initially, we observed that DSS impaired angiogenesis and downregulated endogenous vascular endothelial growth factor B (VEGFB) expression compared to LSS. We further found that the changes in membrane protein, migration and invasion enhancer 1 (MIEN1) play a role in regulating ERK/MAPK signaling, thereby contributing to endothelial angiogenesis in response to FSS. We also showed the involvement of MIEN1-directed cytoskeleton organization. These findings suggest the significance of shear stress in endothelial angiogenesis, thereby enhancing our understanding of the alterations in angiogenesis that occur during the transition from physiological to pathological blood flow.

Multifunctional porous poly (L-lactic acid) nanofiber membranes with enhanced anti-inflammation, angiogenesis and antibacterial properties for diabetic wound healing

With increased diabetes incidence, diabetic wound healing is one of the most common diabetes complications and is characterized by easy infection, chronic inflammation, and reduced vascularization. To address these issues, biomaterials with multifunctional antibacterial, immunomodulatory, and angiogenic properties must be developed to improve overall diabetic wound healing for patients. In our study, we prepared porous poly (L-lactic acid) (PLA) nanofiber membranes using electrospinning and solvent evaporation methods. Then, sulfated chitosan (SCS) combined with polydopamine-gentamicin (PDA-GS) was stepwise modified onto porous PLA nanofiber membrane surfaces. Controlled GS release was facilitated via dopamine self-polymerization to prevent early stage infection. PDA was also applied to PLA nanofiber membranes to suppress inflammation. In vitro cell tests results showed that PLA/SCS/PDA-GS nanofiber membranes immuomodulated macrophage toward the M2 phenotype and increased endogenous vascular endothelial growth factor secretion to induce vascularization. Moreover, SCS-contained PLA nanofiber membranes also showed good potential in enhancing macrophage trans-differentiation to fibroblasts, thereby improving wound healing processes. Furthermore, our in vitro antibacterial studies against Staphylococcus aureus indicated the effective antibacterial properties of the PLA/SCS/PDA-GS nanofiber membranes. In summary, our novel porous PLA/SCS/PDA-GS nanofiber membranes possessing enhanced antibacterial, anti-inflammatory, and angiogenic properties demonstrate promising potential in diabetic wound healing processes.

VEGF affects mitochondrial ROS generation in glioma cells and acts as a radioresistance factor.

Vascular endothelial growth factor (VEGF) is closely related to angiogenesis. Anticancer therapy by inhibiting VEGF signaling is well established. However, the role of VEGF in cell-cell communication during the response to ionizing radiation is not well understood. Here, we examined the role of VEGF on radiosensitivity of cells. The addition of recombinant VEGF (rVEGF) on cultured rat C6 glioma cells showed a radioprotective effects on X-ray irradiation and reduced oxidative stress. These effects were also observed by endogenous VEGF in supernatant of C6 glioma cells. Reduction of oxidative stress by VEGF is suggested to underlie the radioprotective effects. The mechanism of VEGF-induced reduction of oxidative stress was indicated by a decreased oxygen consumption rate (OCR) in mitochondria. However, the number of DNA double-strand breaks (DSB) immediately after irradiation was not reduced by the treatment with VEGF. These results suggest that VEGF plays a role in cell survival after irradiation by controlling the oxidative condition through mitochondrial function that is independent of the efficiency of DSB induction.

YAP‐Suppressive Nanodrug Crosslinked Self‐Immunoregulatory Polysaccharide Injectable Hydrogel for Attenuating Cardiac Fibrosis to Treat Myocardial Infarction

AbstractThe cardiac fibrosis caused by excessive deposition of collagen and the fibro‐inflammatory cascade reaction severely impedes the cardiac regenerative efficiency after myocardial infarction (MI) so that the onefold treating target is far from satisfying therapeutic efficacy. Herein, a yes‐associated protein (YAP)‐suppressive nanodrug‐crosslinked self‐immunoregulatory polysaccharide injectable hydrogel is fabricated for the first time. To this end, cationic liposomes loading YAP inhibitor verteporfin (Lipo‐VP) is prepared and coated with oxidized fucoidan (OFu), a unique anti‐inflammation polysaccharide, to form anti‐fibrotic and immunoregulatory nanodrug (OFu‐Lipo‐VP). The coated fucoidan itself acts as a reactive oxygen species (ROS) scavenger and inflammation regulator, thus facilitating angiogenesis function by eliciting endogenous vascular endothelial growth factor secretion of macrophages. Then an injectable hydrogel (termed as OFu‐Lipo‐VP‐PGA) is formed through addition reaction between the aldehyde groups of OFu‐Lipo‐VP and the thiol groups of thiol‐modified poly(γ‐glutamic acid) (PGA‐SH), where the thiol groups can also aid in eliminating ROS. The acute MI models are established and the infarcted male rats are treated with this injectable OFu‐Lipo‐VP‐PGA hydrogel after MI. The outcomes at 28 days post‐surgery indicate efficient restoration of cardiac functions and attenuation of cardiac fibrosis. This study opens up a new possibility for MI treatment with immunoregulatory and antifibrotic injectable polysaccharide‐based hydrogel.

Induction of angiogenesis and neural progenitor cells by basic fibroblast growth factor-releasing polyglycolic acid sheet following focal cerebral infarction in mice.

Biodegradable sheets loaded with basic fibroblast growth factor (bFGF) are prepared as novel bFGF-releasing systems from polyglycolic acid nonwoven fabric by oxygen plasma treatment followed by bFGF adsorption. In the present study, we investigated the therapeutic effects of this system on a focal cerebral infarction model (CB-17 mouse). A preliminary in vitro study showed that this system released bFGF in an acellular culture medium, thereby keeping the bFGF concentration in the medium at ≥5ng/ml for a prolonged period of 7 days. The released bFGF from this system retained its biological activity to enhance endothelial tube formation in vitro. In a mouse model of subacute focal cerebral infarction, this system increased the expression of endogenous vascular endothelial growth factor in the peri-infarct cortex and subventricular zone, promoted angiogenesis in the striatum, and increased neural progenitor cells in the peri-infarct cortex. Thus, this bFGF-releasing system has the potential to be a novel therapeutic approach for cerebral infarction.

Protective role of VEGF/VEGFR2 signaling against high fatality associated with hepatic encephalopathy via sustaining mitochondrial bioenergetics functions

BackgroundThe lack of better understanding of the pathophysiology and cellular mechanisms associated with high mortality seen in hepatic encephalopathy (HE), a neurological complication arising from acute hepatic failure, remains a challenging medical issue. Clinical reports showed that the degree of baroreflex dysregulation is related to the severity of HE. Furthermore, mitochondrial dysfunction in the rostral ventrolateral medulla (RVLM), a key component of the baroreflex loop that maintains blood pressure and sympathetic vasomotor tone, is known to underpin impairment of baroreflex. Realizing that in addition to angiogenic and vasculogenic effects, by acting on its key receptor (VEGFR2), vascular endothelial growth factor (VEGF) elicits neuroprotection via maintenance of mitochondrial function, the guiding hypothesis of the present study is that the VEGF/VEGFR2 signaling plays a protective role against mitochondrial dysfunction in the RVLM to ameliorate baroreflex dysregulation that underpins the high fatality associated with HE.MethodsPhysiological, pharmacological and biochemical investigations were carried out in proof-of-concept experiments using an in vitro model of HE that involved incubation of cultured mouse hippocampal neurons with ammonium chloride. This was followed by corroboratory experiments employing a mouse model of HE, in which adult male C57BL/6 mice and VEGFR2 wild-type and heterozygous mice received an intraperitoneal injection of azoxymethane, a toxin used to induce acute hepatic failure.ResultsWe demonstrated that VEGFR2 is present in cultured neurons, and observed that whereas recombinant VEGF protein maintained cell viability, gene-knockdown of vegfr2 enhanced the reduction of cell viability in our in vitro model of HE. In our in vivo model of HE, we found that VEGFR2 heterozygous mice exhibited shorter survival rate and time when compared to wild-type mice. In C57BL/6 mice, there was a progressive reduction in VEGFR2 mRNA and protein expression, mitochondrial membrane potential and ATP levels, alongside augmentation of apoptotic cell death in the RVLM, accompanied by a decrease in baroreflex-mediated sympathetic vasomotor tone and hypotension. Immunoneutralization of VEGF exacerbated all those biochemical and physiological events.ConclusionsOur results suggest that, acting via VEGFR2, the endogenous VEGF plays a protective role against high fatality associated with HE by amelioration of the dysregulated baroreflex-mediated sympathetic vasomotor tone through sustaining mitochondrial bioenergetics functions and eliciting antiapoptotic action in the RVLM.

VEGF, a Key Factor for Blood Brain Barrier Injury After Cerebral Ischemic Stroke.

Blood brain barrier (BBB) injury is an important factor affecting the prognosis of ischemic stroke. Extensive research on BBB injury has revealed that blood vessels and neural networks are interdependent and interrelated during and after the development of the brain. An array of signaling molecules, known as angioneurins, can affect both blood vessels and neural networks simultaneously. Angioneurins not only regulate the angiogenesis and remodeling process of the vascular system, but also act as neurotrophic and neuroprotective factors, or serve as guide molecules for axons. Vascular endothelial growth factor (VEGF) is a type of angioneurin that is expressed in neurons, astrocytes, macrophages, and vascular endothelial cells in ischemic and hypoxic brain tissues after cerebral ischemia. VEGF can increase and induce the destruction of the endothelial barrier in the early stages of cerebral ischemia. Both the upregulation of endogenous VEGF levels and the use of exogenous VEGF are harmful in the acute stage of stroke. However, the harmful effects of VEGF on vascular integrity are transient. Several studies have shown that VEGF regulates angiogenesis, neurogenesis, neurite growth and brain edema after cerebral ischemia. Therefore, it is crucial to understand the dual role of VEGF in ischemic stroke. The following will focus on the damage caused by VEGF to the BBB in the context of cerebral ischemic stroke, as well as therapeutic studies targeting VEGF.

The Role of Vascular Endothelial Growth Factor in Tendon Healing.

Angiogenesis is crucial to facilitate tendon healing, such as delivering oxygen and nutrients, removing waste products, and controlling immune responses. Vascular endothelial growth factor (VEGF) is one of the most vital angiogenic factors that regulate blood vessel formation in tendon healing. Recently, biological therapies, including the application of exogenous VEGF, have been attracting increasing attention. However, at present, the effect of the application of exogenous VEGF in tendon healing is controversial, as the role of endogenous VEGF in tendons has also not been fully elucidated. This article will summarize the role of both endogenous and exogenous VEGF in tendon healing and discuss possible reasons for the controversy. The present review shows that tendon repair is facilitated only by proper angiogenesis and VEGF at the early stage, whereas the persistent high VEGF expression and prolonged presence of blood vessels may impair tendon repair at a later stage.

VEGF Maintains Maternal Vascular Space Homeostasis in the Mouse Placenta through Modulation of Trophoblast Giant Cell Functions.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that acts primarily on endothelial cells, but numerous studies suggest that VEGF also acts on non-endothelial cells, including trophoblast cells. Inhibition of VEGF signaling by excess production of the endogenous soluble VEGF receptor sFlt1 in trophoblast cells has been implicated in several pregnancy complications. Our previous studies and other reports have shown that VEGF directly regulates placental vascular development and functions and that excess VEGF production adversely affects placental vascular development. Trophoblast giant cells (TGCs) line the maternal side of the placental vasculature in mice and function like endothelial cells. In this study, we specifically examined the effect of excess VEGF signaling on TGC development associated with defective placental vascular development using two mouse models an endometrial VEGF overexpression model and a placenta-specific sFlt1 knockdown model. Placentas of endometrial VEGF-overexpressing dams at embryonic days (E) 11.5 and 14.5 showed dramatic enlargement of the venous maternal spaces in junctional zones. The size and number of the parietal TGCs that line these venous spaces in the placenta were also significantly increased. Although junctional zone venous blood spaces from control and VEGF-overexpressing dams were not markedly different in size at E17.5, the number and size of P-TGCs were both significantly increased in the placentas from VEGF-overexpressing dams. In sFlt1 knockdown placentas, however, there was a significant increase in the size of the sinusoidal TGC-lined, alkaline phosphatase-positive maternal blood spaces in the labyrinth. These results suggest that VEGF signaling plays an important role in maintaining the homeostasis of the maternal vascular space in the mouse placenta through modulation of TGC development and differentiation, similar to the effect of VEGF on endothelial cells in other vascular beds.

Collagen sponge prolongs taurine release for improved wound healing through inflammation inhibition and proliferation stimulation.

BackgroundAttenuating oxidative stress response is an effective strategy for the treatment of wounds. Taurine is a widely abundant amino acid in mammal species, capable of inhibiting oxygen-free radicals during the inflammation phase.MethodsA novel taurine carried biocompatible composite collagen-derived sponge, Tau@Col, was fabricated for the treatment of a full-thickness removal mouse wounds model. In vitro experiments included taurine release from Tau@Col and cell viability when co-cultured with Tau@Col. With the prolonged release of taurine upon the wound site, Tau@Col was engineered to perform well in the wound site through inflammation inhibition and proliferation stimulation as demonstrated by a series of histological staining.ResultsIn vitro taurine release profile and good cell biocompatibility of Tau@Col were demonstrated. In vivo studies showed that Tau@Col indeed sped up the process of wound regeneration through enhanced granulation formation, collagen deposition as well as re-epithelialization. Further investigations through immunofluorescence staining revealed that the improved wound healing ability of Tau@Col was mediated by the enhanced cell proliferation via the upregulation of endogenous vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β) expression as well as decreased inflammatory response through stimulated M2 polarization of macrophages.ConclusionsThis engineered Tau@Col delivery system has great potential as a wound dressing in future applications.

The Prominin-1-Derived Peptide Improves Cardiac Function Following Ischemia.

Myocardial infarction (MI) remains the leading cause of death in the western world. Despite advancements in interventional revascularization technologies, many patients are not candidates for them due to comorbidities or lack of local resources. Non-invasive approaches to accelerate revascularization within ischemic tissues through angiogenesis by providing Vascular Endothelial Growth Factor (VEGF) in protein or gene form has been effective in animal models but not in humans likely due to its short half-life and systemic toxicity. Here, we tested the hypothesis that PR1P, a small VEGF binding peptide that we developed, which stabilizes and upregulates endogenous VEGF, could be used to improve outcome from MI in rodents. To test this hypothesis, we induced MI in mice and rats via left coronary artery ligation and then treated animals with every other day intraperitoneal PR1P or scrambled peptide for 14 days. Hemodynamic monitoring and echocardiography in mice and echocardiography in rats at 14 days showed PR1P significantly improved multiple functional markers of heart function, including stroke volume and cardiac output. Furthermore, molecular biology and histological analyses of tissue samples showed that systemic PR1P targeted, stabilized and upregulated endogenous VEGF within ischemic myocardium. We conclude that PR1P is a potential non-invasive candidate therapeutic for MI.

A Method of Manufacturing a Long-Acting Medicinal Film Containing VEGF

Background. The development of new methods for delivering biologically active substances to the surgical site is a promising area of modern surgery. One of the biologically active substances used to stimulate regeneration is the vascular endothelial growth factor (VEGF). The search for ways to gradually and over a long period of time deliver VEGF to the surgical site is a promising area of research. Aim. To develop a method for delivering VEGF to the surgical site and to assess its elimination in the early postoperative period. Materials and methods. The study included 78 male Wistar rats at the age of 10 months. All animals underwent reconstructive surgery on the trachea, the animals were divided into 3 groups: group 1 – without a medicinal film, group 2 – with a medicinal film of prolonged action, group 3 – with a medicinal film of prolonged action containing VEGF. Blood sampling was carried out on days 1, 3, and 21 of the study, using the method of enzyme-linked immunosorbent assay to determine the level of VEGF in blood plasma, the unit of measurement was pg/ml. Results . A long-acting medicinal film containing VEGF has been developed. It was revealed that the use of a medicinal film containing VEGF significantly increases the VEGF index in blood plasma by 26 times starting from the first day of the study and remained high throughout the study. Conclusion . The results obtained indicate the effectiveness of the developed medicinal film of prolonged action. Elimination of VEGF starts from the first day of the study and lasts up to 21 days. High VEGF indices, according to the authors, are associated with the exogenous introduction of VEGF into the animal organism in the form of a prolonged-action film and the induction of endogenous VEGF in rats.

PR1P Stabilizes VEGF and Upregulates Its Signaling to Reduce Elastase-induced Murine Emphysema.

Emphysema is a progressive and fatal lung disease with no cure that is characterized by thinning, enlargement, and destruction of alveoli, leading to impaired gas exchange. Disease progression is due in part to dysregulation of VEGF (vascular endothelial growth factor) signaling in the lungs and increased lung-cell apoptosis. Here we asked whether PR1P (Prominin-1-derived peptide), a novel short peptide we designed that increases VEGF binding to endothelial cells, could be used to improve outcome in in vitro and in vivo models of emphysema. We used computer simulation and in vitro and in vivo studies to show that PR1P upregulated endogenous VEGF receptor-2 signaling by binding VEGF and preventing its proteolytic degradation. In so doing, PR1P mitigated toxin-induced lung-cell apoptosis, including from cigarette-smoke extract in vitro and from LPS in vivo in mice. Remarkably, inhaled PR1P led to significantly increased VEGF concentrations in murine lungs within 30 minutes that remained greater than twofold above that of control animals 24 hours later. Finally, inhaled PR1P reduced acute lung injury in 4- and 21-day elastase-induced murine emphysema models. Taken together, these results highlight the potential of PR1P as a novel therapeutic agent for the treatment of emphysema or other lung diseases characterized by VEGF signaling dysregulation.

One Step Closer to a Cure for Preeclampsia?

One Step Closer to a Cure for Preeclampsia?

Exploiting synergistic effect of externally loaded bFGF and endogenous growth factors for accelerated wound healing using heparin functionalized PCL/gelatin co-spun nanofibrous patches

Growth factors (GFs) are signaling molecules that are principle mediators in tissue regeneration. Biomaterial scaffolds employed as wound dressings are often hampered by their limitations to deliver GFs exogenously due to their instability and low half-life. The key to overcome this challenge lies in the better organization and use of endogenous pro-regenerative GFs released at regenerative site, with an aim to minimize the sole dependency on exogenous factors. Considering such challenges, this research utilizes the exogenous and endogenous GFs sequestering capability of heparin functionalized PCL/gelatin co-spun nanofabrics to mediate synergistically driven tissue regeneration by utilizing combined therapeutic effect of exogenous and endogenous GFs, and thereby minimizing the sole dependency on exogenous GFs for tissue regeneration. Basic fibroblast growth factor (bFGF) was chosen as GF for exogenous loading whereas vascular endothelial growth factor (VEGF) was chosen as a representative example to demonstrate the endogenous pro-regenerative GF sequestration capability of fabricated nanofabrics. From our results, the fabricated nanofabrics showed loading efficiency of 80% for exogenous bFGF and can sequester 15-fold more amount of endogenous VEGF compared to non-heparin functionalized nanofibrous dressings. When applied as wound dressings, heparin functionalized nanofibers showed better therapeutic capability compared to control groups that were treated using patches without heparin functionalization, indicating endogenously driven tissue regeneration. This was indicated by significant higher number of newly formed skin appendages, lesser scarring and lower inflammatory levels in newly formed granulation. Additionally, further improvements in therapeutic effect was observed when exogenous bFGF was employed indicating effectiveness of synergistically mediated tissue regeneration.

Roxadustat (FG-4592) accelerates pulmonary growth, development, and function in a compensatory lung growth model.

Children with hypoplastic lung disease associated with congenital diaphragmatic hernia (CDH) continue to suffer significant morbidity and mortality secondary to progressive pulmonary disease. Current management of CDH is primarily supportive and mortality rates of the most severely affected children have remained unchanged in the last few decades. Previous work in our lab has demonstrated the importance of vascular endothelial growth factor (VEGF)-mediated angiogenesis in accelerating compensatory lung growth. In this study, we evaluated the potential for Roxadustat (FG-4592), a prolyl hydroxylase inhibitor known to increase endogenous VEGF, in accelerating compensatory lung growth. Treatment with Roxadustat increased lung volume, total lung capacity, alveolarization, and exercise tolerance compared to controls following left pneumonectomy. However, this effect was likely modulated not only by increased VEGF, but rather also by decreased pigment epithelium-derived factor (PEDF), an anti-angiogenic factor. Furthermore, this mechanism of action may be specific to Roxadustat. Vadadustat (AKB-6548), a structurally similar prolyl hydroxylase inhibitor, did not demonstrate accelerated compensatory lung growth or decreased PEDF expression following left pneumonectomy. Given that Roxadustat is already in Phase III clinical studies for the treatment of chronic kidney disease-associated anemia with minimal side effects, its use for the treatment of pulmonary hypoplasia could potentially proceed expeditiously.

Self-assembled dodecyl group-modified gelatin microparticle-based hydrogels with angiogenic properties

Supplying oxygen and nutrients to implanted cells or tissues is an important factor that improves their survivability and function in regenerative medicine. Various efforts have been made to develop angiogenic materials by incorporating and releasing growth factors such as vascular endothelial growth factor (VEGF). However, these exogenous growth factors have a short half-life under physiological conditions. We therefore designed a novel angiogenic microparticle (C12-MP) comprising Alaska pollock-derived gelatin (ApGltn) modified with a dodecyl group (C12-ApGltn) to stimulate endogenous VEGF secretion. The C12-MP suspension formed an injectable hydrogel, the rheological properties and enzymatic degradation of which were evaluated. RAW264 cells, mouse macrophage-like cells, cultured with C12-MPs, secreted significantly more VEGF than the original ApGltn MPs. Based on laser Doppler perfusion imaging, the C12-MP hydrogel clearly induced increased blood perfusion in a subcutaneous mouse model compared with the original ApGltn microparticle (Org-MP) or phosphate-buffered saline controls. Histological studies revealed that the areas of nuclear factor (NF)-κB, CD31, and myeloperoxidase staining showed a greater increase at the site injected with C12-MPs than at the site injected with the original ApGltn microparticles or phosphate-buffered saline. The C12-MP hydrogel is a promising angiogenic material for constructing vascular beds for cell transplantation by promoting endogenous VEGF secretion without additional growth factors.

A hydrophobic gelatin fiber sheet promotes secretion of endogenous vascular endothelial growth factor and stimulates angiogenesis.

In tissue engineering and regenerative medicine, the formation of vascular beds is an effective method to supply oxygen and nutrients to implanted cells or tissues to improve their survival and promote normal cellular functions. Various types of angiogenic materials have been developed by incorporating growth factors, such as vascular endothelial growth factor, in biocompatible materials. However, these exogenous growth factors suffer from instability and inactivation under physiological conditions. In this study, we designed a novel angiogenic electrospun fiber sheet (C16-FS) composed of Alaska pollock-derived gelatin (ApGltn) modified with hexadecyl (C16) groups to induce localized and sustained angiogenesis without growth factors. C16-FS was thermally crosslinked to enhance its stability. We demonstrated that C16-FS swells in phosphate-buffered saline for over 24 h and resists degradation. Laser doppler perfusion imaging showed that C16-FS induced increased blood perfusion when implanted subcutaneously in rats compared with unmodified ApGltn-fiber sheets (Org-FS) and the sham control. Furthermore, angiogenesis was sustained for up to 7 days following implantation. Immunohistochemical studies revealed elevated nuclear factor-κB and CD31 levels around the C16-FS implantation site compared with the Org-FS implantation site and the control incision site. These results demonstrate that C16-FS is a promising angiogenic material to promote the formation of vascular beds for cell and tissue transplantation without the need for growth factors.

Growth factor-free, angiogenic hydrogel based on hydrophobically modified Alaska pollock gelatin.

Angiogenesis is important for supplying oxygen and nutrients to implanted cells and organs and thereby promoting their survival. However, exogenously administered growth factors such as vascular endothelial growth factor (VEGF) have a short half-life and are unstable under physiological conditions. In the present study, we developed an angiogenesis-inducing hydrogel by modifying Alaska pollock-derived gelatin with a dodecyl group (C12-ApGltn), and demonstrated that it is biodegradable and highly fluid at room temperature (25°C). C12-ApGltn dissolved in phosphate-buffered saline at 20 w/v% formed a self-assembling hydrogel with thixotropic properties that stimulated VEGF secretion by macrophage-like RAW264 cells. Moreover, C12-ApGltn stimulated nuclear factor-κB and VEGF expression when subcutaneously injected into mice and increased the cluster of differentiation 31-positive area compared with injection of unmodified ApGltn and phosphate-buffered saline control in the absence of any growth factors. Hematoxylin and eosin staining confirmed vascular capillaries around the C12-ApGltn injection site. These results demonstrate that C12-ApGltn hydrogel is a promising angiogenic material for clinical applications that can stimulate endogenous VEGF expression without requiring additional growth factors.

Pediatric Pulmonary Hypertension on the World Stage: Do We Need Separate Neonatal Guidelines?

Pediatric Pulmonary Hypertension on the World Stage: Do We Need Separate Neonatal Guidelines?