Impaired Angiogenesis Research Articles

Gases and gas-releasing materials for the treatment of chronic diabetic wounds.

Chronic non-healing wounds are a common consequence of skin ulceration in diabetic patients, with severe cases such as diabetic foot even leading to amputations. The interplay between pathological factors like hypoxia-ischemia, chronic inflammation, bacterial infection, impaired angiogenesis, and accumulation of advanced glycosylation end products (AGEs), resulting from the dysregulation of the immune microenvironment caused by hyperglycemia, establishes an unending cycle that hampers wound healing. However, there remains a dearth of sufficient and effective approaches to break this vicious cycle within the complex immune microenvironment. Consequently, numerous scholars have directed their research efforts towards addressing chronic diabetic wound repair. In recent years, gases including Oxygen (O2), Nitric oxide (NO), Hydrogen (H2), Hydrogen sulfide (H2S), Ozone (O3), Carbon monoxide (CO) and Nitrous oxide (N2O), along with gas-releasing materials associated with them have emerged as promising therapeutic solutions due to their ability to regulate angiogenesis, intracellular oxygenation levels, exhibit antibacterial and anti-inflammatory effects while effectively minimizing drug residue-induced damage and circumventing drug resistance issues. In this review, we discuss the latest advances in the mechanisms of action and treatment of these gases and related gas-releasing materials in diabetic wound repair. We hope that this review can provide different ideas for the future design and application of gas therapy for chronic diabetic wounds.

Bioinspired soft-hard combined system with mild photothermal therapeutic activity promotes diabetic bone defect healing via synergetic effects of immune activation and angiogenesis.

Background: The comprehensive management of diabetic bone defects remains a substantial clinical challenge due to the hostile regenerative microenvironment characterized by aggravated inflammation, excessive reactive oxygen species (ROS), bacterial infection, impaired angiogenesis, and unbalanced bone homeostasis. Thus, an advanced multifunctional therapeutic platform capable of simultaneously achieving immune regulation, bacterial elimination, and tissue regeneration is urgently designed for augmented bone regeneration under diabetic pathological milieu. Methods and Results: Herein, a photoactivated soft-hard combined scaffold system (PGCZ) was engineered by introducing polydopamine-modified zeolitic imidazolate framework-8-loaded double-network hydrogel (soft matrix component) into 3D-printed poly(ε-caprolactone) (PCL) scaffold (hard matrix component). The versatile PGCZ scaffold based on double-network hydrogel and 3D-printed PCL was thus prepared and features highly extracellular matrix-mimicking microstructure, suitable biodegradability and mechanical properties, and excellent photothermal performance, allowing long-term structural stability and mechanical support for bone regeneration. Under periodic near-infrared (NIR) irradiation, the localized photothermal effect of PGCZ triggers the on-demand release of Zn2+, which, together with repeated mild hyperthermia, collectively accelerates the proliferation and osteogenic differentiation of preosteoblasts and potently inhibits bacterial growth and biofilm formation. Additionally, the photoactivated PGCZ system also presents outstanding immunomodulatory and ROS scavenging capacities, which regulate M2 polarization of macrophages and drive functional cytokine secretion, thus leading to a pro-regenerative microenvironment in situ with enhanced vascularization. In vivo experiments further demonstrated that the PGCZ platform in conjunction with mild photothermal therapeutic activity remarkably attenuated the local inflammatory cascade, initiated endogenous stem cell recruitment and neovascularization, and orchestrated the osteoblast/osteoclast balance, ultimately accelerating diabetic bone regeneration. Conclusions: This work highlights the potential application of a photoactivated soft-hard combined system that provides long-term biophysical (mild photothermal stimulation) and biochemical (on-demand ion delivery) cues for accelerated healing of diabetic bone defects.

Mesenchymal stem cell-derived extracellular vesicles accelerate diabetic wound healing by inhibiting NET-induced ferroptosis of endothelial cells.

Impaired angiogenesis is a major factor contributing to delayed wound healing in diabetes. Dysfunctional mitochondria promote the formation of neutrophil extracellular traps (NETs), obstructing angiogenesis during wound healing. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown promise in promoting tissue repair and regeneration in diabetes; however, the precise pathways involved in this process remain unclear. In this study, NET-induced ferroptosis of endothelial cells (ECs) and angiogenesis were assessed in diabetic wound samples from both patients and animal models. In vitro and in vivo experiments were performed to examine the regulatory mechanisms of NETs in ECs using specific inhibitors and gene-knockout mice. MSC-EVs encapsulating dysfunctional mitochondria were used to trigger mitochondrial fusion and restore mitochondrial function in neutrophils to suppress NET formation. Angiogenesis in wound tissue was evaluated using color laser Doppler imaging and vascular density analysis. Wound healing was evaluated via macroscopic analysis and histological evaluation of the epithelial gap. NET-induced ferroptosis of ECs was validated as a crucial factor contributing to the impairment of angiogenesis in diabetic wounds. Mechanistically, NETs regulated ferroptosis by suppressing the PI3K/AKT pathway. Furthermore, MSC-EVs transferred functional mitochondria to neutrophils in wound tissue, triggered mitochondrial fusion, and restored mitochondrial function, thereby reducing NET formation. These results suggest that inhibiting NET formation and EC ferroptosis or activating the PI3K/AKT pathway can remarkably improve wound healing. In conclusion, this study reveals a novel NET-mediated pathway involved in wound healing in diabetes and suggests an effective therapeutic strategy for accelerating wound healing.

Strategies to overcome tumor microenvironment immunosuppressive effect on the functioning of CAR-T cells in high-grade glioma.

Despite significant progress in the treatment of some types of cancer, high-grade gliomas (HGGs) remain a significant clinical problem. In the case of glioblastoma (GBM), the most common solid tumor of the central nervous system in adults, the average survival time from diagnosis is only 15-18 months, despite the use of intensive multimodal therapy. Chimeric antigen receptor (CAR)-expressing T cells, which have already been approved by the Food and Drug Administration for use in the treatment of certain hematologic malignancies, are a new, promising therapeutic option. However, the efficacy of CAR-T cells in solid tumors is lower due to the immunosuppressive tumor microenvironment (TME). Reprogramming the immunosuppressive TME toward a pro-inflammatory phenotype therefore seems particularly important because it may allow for increasing the effectiveness of CAR-T cells in the therapy of solid tumors. The following literature review aims to present the results of preclinical studies showing the possibilities of improving the efficacy of CAR-T in the TME of GBM by reprogramming the TME toward a pro-inflammatory phenotype. It may be achievable thanks to the use of CAR-T in a synergistic therapy in combination with oncolytic viruses, radiotherapy, or epigenetic inhibitors, as well as by supporting CAR-T cells crossing of the blood-brain barrier, normalizing impaired angiogenesis in the TME, improving CAR-T effector functions by cytokine signaling or by blocking/knocking out T-cell inhibitors, and modulating the microRNA expression. The use of CAR-T cells modified in this way in synergistic therapy could lead to the longer survival of patients with HGG by inducing an endogenous anti-tumor response.

Hair Loss in a Hemodialysis Patient after Repetitive Use of the Antipruritic Drug Nalfurafine: Implications of Impaired Angiogenesis for Hair Loss.

A 47-year-old man who presented with scalp hair loss was transferred to our dialysis facility 3 months after hemodialysis initiation. He noticed systemic hair loss one month after the initiation of dialysis. Because the antipruritic drug nalfurafine was the only drug that had been newly added to his regular medication after he started hemodialysis, we stopped its prescription. His hair loss was completely ameliorated for the next five months. We speculated that κ-opioid receptor activation by nalfurafine caused blood capillary regression around the hair follicles, leading to cessation of hair growth and subsequent hair fallout.

Molecular characterization of chronic cutaneous wounds reveals subregion- and wound type-specific differential gene expression.

A limited understanding of the pathology underlying chronic wounds has hindered the development of effective diagnostic markers and pharmaceutical interventions. This study aimed to elucidate the molecular composition of various common chronic ulcer types to facilitate drug discovery strategies. We conducted a comprehensive analysis of leg ulcers (LUs), encompassing venous and arterial ulcers, foot ulcers (FUs), pressure ulcers (PUs), and compared them with surgical wound healing complications (WHCs). To explore the pathophysiological mechanisms and identify similarities or differences within wounds, we dissected wounds into distinct subregions, including the wound bed, border, and peri-wound areas, and compared them against intact skin. By correlating histopathology, RNA sequencing (RNA-Seq), and immunohistochemistry (IHC), we identified unique genes, pathways, and cell type abundance patterns in each wound type and subregion. These correlations aim to aid clinicians in selecting targeted treatment options and informing the design of future preclinical and clinical studies in wound healing. Notably, specific genes, such as PITX1 and UPP1, exhibited exclusive upregulation in LUs and FUs, potentially offering significant benefits to specialists in limb preservation and clinical treatment decisions. In contrast, comparisons between different wound subregions, regardless of wound type, revealed distinct expression profiles. The pleiotropic chemokine-like ligand GPR15L (C10orf99) and transmembrane serine proteases TMPRSS11A/D were significantly upregulated in wound border subregions. Interestingly, WHCs exhibited a nearly identical transcriptome to PUs, indicating clinical relevance. Histological examination revealed blood vessel occlusions with impaired angiogenesis in chronic wounds, alongside elevated expression of genes and immunoreactive markers related to blood vessel and lymphatic epithelial cells in wound bed subregions. Additionally, inflammatory and epithelial markers indicated heightened inflammatory responses in wound bed and border subregions and reduced wound bed epithelialization. In summary, chronic wounds from diverse anatomical sites share common aspects of wound pathophysiology but also exhibit distinct molecular differences. These unique molecular characteristics present promising opportunities for drug discovery and treatment, particularly for patients suffering from chronic wounds. The identified diagnostic markers hold the potential to enhance preclinical and clinical trials in the field of wound healing.

Chlorogenic acid supported strontium polyphenol networks ensemble microneedle patch to promote diabetic wound healing

Delayed or non-healing of diabetic wounds is a significant complication, often attributed to high glucose-induced M1 macrophage accumulation, impaired angiogenesis, and reactive oxygen species (ROS) buildup. Addressing this, we introduced a strontium polyphenol network microneedle patch (SrC-MPNs@MN-PP) for percutaneous drug delivery. This patch, formulated with polymer poly(γ-glutamic acid) (γ-PGA) and epsilon-poly-l-lysine (ε-PLL), incorporates strontium polyphenol networks (SrC-MPNs). The release of chlorogenic acid (CGA) from SrC-MPNs not only neutralizes ROS, but strontium ions also foster angiogenesis. Consequently, SrC-MPNs@MN-PP can ameliorate the diabetic wound microenvironment and expedite healing.

Type I Interferons induce endothelial destabilization in Systemic Lupus Erythematosus in a Tie2-dependent manner.

Endothelial cell (EC) dysfunction is a hallmark of Systemic Lupus Erythematosus (SLE) and Tie2 is a receptor essential for vascular stability. Inflammatory processes promote inhibition of Tie2 homeostatic activation, driving vascular dysfunction. In this work we determined whether type I Interferons (IFN) induce Tie2 signalling-mediated endothelial dysfunction in patients with SLE. Serum levels of Angiopoietin (Ang)-1, Ang-2 and soluble (s)Tie1 in patients with SLE and healthy controls were measured by ELISA. Monocytes from patients with SLE and Human Umbilical Vein EC (HUVEC) were stimulated with IFN-α, IFN-β (1000 I.U.) or SLE serum (20%). mRNA and protein expression, phosphorylation and translocation were determined by quantitative PCR, ELISA, Western Blot, flow cytometry and confocal microscopy. Viability and angiogenic capacity were determined by calcein and tube formation assays. We found that sTie1 and Ang-2 serum levels were increased and Ang-1 decreased in patients with SLE and were associated with clinical characteristics. Type I IFN significantly decreased Ang-1 and increased Ang-2 in monocytes from patients with SLE. Type I IFN increased sTie1 and Ang-2 secretion and reduced Tie2 activation in HUVEC. Functionally, type I IFN significantly reduced EC viability and impaired angiogenesis in a Tie2 signalling-dependent manner. Finally, SLE serum increased Ang-2 and sTie1 secretion and significantly decreased tube formation. Importantly, Tie1 and IFNAR1 knockdown reversed these effects in tube formation. Overall, type I IFN play an important role in the stability of EC by inhibiting Tie2 signalling, suggesting that these processes may be implicated in the cardiovascular events observed in patients with SLE.

Oleanolic acid rescues critical features of umbilical vein endothelial cells permanently affected by hyperglycemia.

Skin wound healing is a physiological process that involves several cell types. Among them, endothelial cells are required for inflammation resolution and neo-angiogenesis, both necessary for tissue restoration after injury. Primary human umbilical vein endothelial cells (C-HUVECs) are derived from the umbilical cord. When women develop gestational diabetes, chronic exposure to hyperglycemia induces epigenetic modifications in these cells (GD-HUVECs), leading to a permanent pro-inflammatory phenotype and impaired angiogenesis in contrast to control cells. Oleanolic acid (OA) is a bioactive triterpenoid known for its epithelial cell migration promotion stimulation and higher tensile strength of wounds. However, the potentially anti-inflammatory and pro-angiogenic properties of OA are still under investigation. We tested OA on C- and GD-HUVECs under inflammatory conditions induced by low levels of the inflammatory cytokine TNF-α. Reduced expression of adhesion molecules VCAM1, ICAM1, and SELE was obtained in OA-pre-treated C- and GD-HUVECs. Additionally, protein VCAM1 levels were also decreased by OA. Coherently, monocyte adhesion assays showed that a lower number of monocytes adhered to GD-HUVEC endothelium under OA pre-treatment when compared to untreated ones. It is noteworthy that OA improved angiogenesis parameters in both phenotypes, being especially remarkable in the case of GD-HUVECs, since OA strongly rescued their poor tube formation behavior. Moreover, endothelial cell migration was improved in C- and GD-HUVECs in scratch assays, an effect that was further confirmed by focal adhesion (FA) remodeling, revealed by paxillin staining on immunocytochemistry assays. Altogether, these results suggest that OA could be an emergent wound healing agent due to its capacity to rescue endothelial malfunction caused by hyperglycemia.

The Landscape of Biomimetic Nanovesicles in Brain Diseases.

Brain diseases, such as brain tumors, neurodegenerative diseases, cerebrovascular diseases, and brain injuries, are caused by various pathophysiological changes, which pose a serious health threat. Brain disorders are often difficult to treat due to the presence of the blood-brain barrier (BBB). Biomimetic nanovesicles (BNVs), including endogenous extracellular vesicles (EVs) derived from various cells and artificial nanovesicles, possess the ability to penetrate the BBB and thus can be utilized for drug delivery to the brain. BNVs, especially endogenous EVs, are widely distributed in body fluids and usually carry various disease-related signal molecules such as proteins, RNA, and DNA, and may also be analyzed to understand the etiology and pathogenesis of brain diseases. This review covers the exhaustive classification and characterization of BNVs and pathophysiological roles involved in various brain diseases, and emphatically focuses on nanotechnology-integrated BNVs for brain disease theranostics, including various diagnosis strategies and precise therapeutic regulations (e.g., immunity regulation, disordered protein clearance, anti-neuroinflammation, neuroregeneration, angiogenesis, and the gut-brain axis regulation). The remaining challenges and future perspectives regarding the nanotechnology-integrated BNVs for the diagnosis and treatment of brain diseases are also discussed and outlined.

Vascularized liver-on-a-chip model to investigate nicotine-induced dysfunction.

The development of physiologically relevant in vitro systems for simulating disease onset and progression and predicting drug metabolism holds tremendous value in reducing drug discovery time and cost. However, many of these platforms lack accuracy in replicating the tissue architecture and multicellular interactions. By leveraging three-dimensional cell culture, biomimetic soft hydrogels, and engineered stimuli, in vitro models have continued to progress. Nonetheless, the incorporation of the microvasculature has been met with many challenges, specifically with the addition of parenchymal cell types. Here, a systematic approach to investigating the initial seeding density of endothelial cells and its effects on interconnected networks was taken and combined with hepatic spheroids to form a liver-on-a-chip model. Leveraging this system, nicotine's effects on microvasculature and hepatic function were investigated. The findings indicated that nicotine led to interrupted adherens junctions, decreased guanosine triphosphate cyclohydrolase 1 expression, impaired angiogenesis, and lowered barrier function, all key factors in endothelial dysfunction. With the combination of the optimized microvascular networks, a vascularized liver-on-a-chip was formed, providing functional xenobiotic metabolism and synthesis of both albumin and urea. This system provides insight into potential hepatotoxicity caused by various drugs and allows for assessing vascular dysfunction in a high throughput manner.

Signalling pathways associated with impaired angiogenesis in Alzheimer’s Disease

AbstractBackgroundBrain perfusion and blood brain barrier (BBB) integrity are reduced in Alzheimer’s disease (AD). We hypothesized that b‐amyloid (Aβ) induces dysfunction of pathways in vascular cells that regulate angiogenesis.MethodWe performed single nucleus RNA sequencing (snRNAseq) of vascular cells isolated from post mortem samples from multiple cortical regions from AD patients (Braak V‐VI) and non‐diseased controls (NDC, Braak 0‐II). We developed a meta‐analytic approach to integrate these data with related publicly available datasets. We performed differential gene expression (DGE) analyses as a categorical comparison of AD vs NDC and as a confound‐controlled regression of transcriptomic alterations by regional total Aβ. We also performed cell‐specific gene co‐expression analyses identify modules differentially expressed in AD relative to NDC.ResultOur results describe differential expression of genes central to pathways sustaining angiogenesis, proliferation and migration of endothelial cells and the integrity of the BBB with either AD or greater pathological protein load. HIF1A and FGF2, proangiogenic molecules which both induce VEGF, are upregulated in EC, consistent the parenchymal hypoxic response shown repeatedly in prior studies. However, components of signalling pathways downstream of VEGFR2 are downregulated, suggesting a pathological block to angiogenesis with greater Aβ load. While the proangiogenic stimuli promote the expression of genes such as PPP3CA and ITPR1, coding for calcineurin, which contribute to VEGF signalling through the PLCγ‐Ca2+ signalling pathway are upregulated in AD, expression of RAC1 and RHOJ, which enable cellular migration and adhesion, is downregulated. While ANGPT2 expression is also upregulated, the angiopoietin receptor (TIE2, coded by TEK) is downregulated. Downregulation of ADAM10 in AD and upregulation of other NOTCH pathway genes with greater Aβ load suggests altered NOTCH signalling.ConclusionOverall, a hypoxic tissue environment in AD is accompanied by dysfunctional angiogenesis related to Aβ load. Evidence for multiple sites of dysfunction were identified, involving impaired angiopoietin responses, vascular cell migration and NOTCH signaling.

Glucose-responsive, antioxidative HA-PBA-FA/EN106 hydrogel enhanced diabetic wound healing through modulation of FEM1b-FNIP1 axis and promoting angiogenesis.

The diabetic wounds remain to be unsettled clinically, with chronic wounds characterized by drug-resistant bacterial infections, compromised angiogenesis and oxidative damage to the microenvironment. To ameliorate oxidative stress and applying antioxidant treatment in the wound site, we explore the function of folliculin-interacting protein 1 (FNIP1), a mitochondrial gatekeeper protein works to alter mitochondrial morphology, reduce oxidative phosphorylation and protect cells from unwarranted ROS accumulation. And our in vitro experiments showed the effects of FNIP1 in ameliorating oxidative stress and rescued impaired angiogenesis of HUVECs in high glucose environment. To realize the drug delivery and local regulation of FNIP1 in diabetic wound sites, a novel designed glucose-responsive HA-PBA-FA/EN106 hydrogel is introduced for improving diabetic wound healing. Due to the dynamic phenylboronate ester structure with a phenylboronic acid group between hyaluronic acid (HA) and phenylboronic acid (PBA), the hydrogel is able to realize a glucose-responsive release of drugs. Fulvic acid (FA) is added in the hydrogel, which not only severs as crosslinking agent but also provides antibacterial and anti-inflammatory abilities. Moreover, the release of FEM1b-FNIP1 axis inhibitor EN106 ameliorated oxidative stress and stimulated angiogenesis through FEM1b-FNIP1 axis regulation. These in vivo and in vitro results demonstrated that accelerated diabetic wounds repair with the use of the HA-PBA-FA/EN106 hydrogel, which may provide a promising strategy for chronic diabetic wound repair.

Conjugated Polymer Composite Nanoparticles Augmenting Photosynthesis-Based Light-Triggered Hydrogel Promotes Chronic Wound Healing.

Diabetic chronic wounds are characterized by local hypoxia, impaired angiogenesis, and bacterial infection. In situ, self-supply of dissolved oxygen combined with the elimination of bacteria is urgent and challenging for chronic nonhealing wound treatment. Herein, an oxygen-generating system named HA-L-NB/PFE@cp involving biological photosynthetic chloroplasts (cp)/conjugated polymer composite nanoparticles (PFE-1-NPs@cp) and light-triggered hyaluronic acid-based (HA-L-NB) hydrogel for promoting diabetic wound healing is introduced. Briefly, conjugated polymer nanoparticles (PFE-1-NPs) possess unique light harvesting ability, which accelerates the electron transport rates in photosystem II (PS II) by energy transfer, elevating photosynthesis beyond natural chloroplasts. The enhanced release of oxygen can greatly relieve hypoxia, promote cell migration, and favor antibacterial photodynamic therapy. Additionally, the injectable hydrogel precursors are employed as a carrier to deliver PFE-1-NPs@cp into the wound. Under light irradiation, they quickly form a gel by S-nitrosylation coupling reaction and in situ anchor on tissues through amine-aldehyde condensation. Both in vitro and in vivo assays demonstrate that the oxygen-generating system can simultaneously relieve wound hypoxia, eliminate bacteria, and promote cell migration, leading to the acceleration of wound healing. This study provides a facile approach to develop an enhanced oxygen self-sufficient system for promoting hypoxic tissue, especially diabetic wound healing.

Multifunctional Regeneration Silicon-Loaded Chitosan Hydrogels for MRSA-Infected Diabetic Wound Healing.

Repeated microbial infection, excess reactive oxygen species (ROS) accumulation, cell dysfunction, and impaired angiogenesis under hyperglycemia severely inhibit diabetic wound healing. Therefore, developing multifunctional wound dressings accommodating the complex microenvironment of diabetic wounds is of great significance. Here, a multifunctional hydrogel (Regesi-CS) is prepared by loading regeneration silicon (Regesi) in the non-crosslinked chitosan (CS) solution, followed by freeze-drying and hydration. As expected, the blank non-crosslinked CS hydrogel (1%) shows great antibacterial activity against Escherichia coli, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA), improves fibroblast migration, and scavenges intracellular ROS. Interestingly, after loading 1% Regesi, the Regesi-CS (1%-1%) hydrogel shows greater antibacterial activity, significantly promotes fibroblasts proliferation and migration, scavenges much more ROS, and substantially protects fibroblasts under oxidative stress, yet Regesi alone has no or even negative effects. In the MRSA-infected diabetic wound model, Regesi-CS (1%-1%) hydrogel effectively promotes wound healing by eliminating bacterial infection, enhancing granulation tissue formation, promoting collagen deposition, and improving angiogenesis. In conclusion, Regesi-CS hydrogel may be a potential wound dressing for the effective treatment and management of chronic diabetic wounds.

Retinoic Acid-PPARα Mediates β-Carotene Resistance to Placental Dysfunction Induced by Deoxynivalenol.

Deoxynivalenol (DON), one of the most polluted mycotoxins in the environment and food, has been proven to have strong embryonic and reproductive toxicities. However, the effects of DON on placental impairment and effective interventions are still unclear. This study investigated the effect of β-carotene on placental functional impairment and its underlying molecular mechanism under DON exposure. Adverse pregnancy outcomes were caused by intraperitoneal injection of DON from 13.5 to 15.5 days of gestation in mice, resulting in higher enrichment of DON in placenta than in other tissue samples. Interestingly, 0.1% β-carotene dietary supplementation could significantly alleviate DON-induced pregnancy outcomes. Additionally, in vivo and in vitro placental barrier models demonstrated the association of DON-induced placental function impairment with placental permeability barrier disruption, angiogenesis impairment, and oxidative stress induction. Moreover, β-carotene regulated DON-induced placental toxicity by activating the expressions of claudin 1, zonula occludens-1, and vascular endothelial growth factor-A through retinoic acid-peroxisome proliferator-activated receptor α signaling.

Biofilm microenvironment triggered self-enhancing photodynamic immunomodulatory microneedle for diabetic wound therapy

The treatment of diabetic wounds faces enormous challenges due to complex wound environments, such as infected biofilms, excessive inflammation, and impaired angiogenesis. The critical role of the microenvironment in the chronic diabetic wounds has not been addressed for therapeutic development. Herein, we develop a microneedle (MN) bandage functionalized with dopamine-coated hybrid nanoparticles containing selenium and chlorin e6 (SeC@PA), which is capable of the dual-directional regulation of reactive species (RS) generation, including reactive oxygen species (ROS) and reactive nitrogen species (RNS), in response to the wound microenvironment. The SeC@PA MN bandage can disrupt barriers in wound coverings for efficient SeC@PA delivery. SeC@PA not only depletes endogenous glutathione (GSH) to enhance the anti-biofilm effect of RS, but also degrades GSH in biofilms through cascade reactions to generate more lethal RS for biofilm eradication. SeC@PA acts as an RS scavenger in wound beds with low GSH levels, exerting an anti-inflammatory effect. SeC@PA also promotes the M2-phenotype polarization of macrophages, accelerating wound healing. This self-enhanced, catabolic and dynamic therapy, activated by the wound microenvironment, provides an approach for treating chronic wounds.

Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease in which pulmonary arterial (PA) endothelial cell (EC) dysfunction is associated with unrepaired DNA damage. BMPR2 is the most common genetic cause of PAH. We report that human PAEC with reduced BMPR2 have persistent DNA damage in room air after hypoxia (reoxygenation), as do mice with EC-specific deletion of Bmpr2 (EC-Bmpr2-/-) and persistent pulmonary hypertension. Similar findings are observed in PAEC with loss of the DNA damage sensor ATM, and in mice with Atm deleted in EC (EC-Atm-/-). Gene expression analysis of EC-Atm-/- and EC-Bmpr2-/- lung EC reveals reduced Foxf1, a transcription factor with selectivity for lung EC. Reducing FOXF1 in control PAEC induces DNA damage and impaired angiogenesis whereas transfection of FOXF1 in PAH PAEC repairs DNA damage and restores angiogenesis. Lung EC targeted delivery of Foxf1 to reoxygenated EC-Bmpr2-/- mice repairs DNA damage, induces angiogenesis and reverses pulmonary hypertension.

Expression of angiogenic factors in the placenta of heme oxygenase-1 deficient mouse embryo

Heme oxygenase 1 (Hmox1), the inducible form of heme degrading enzymes Hmoxs, is important for establishment and maintenance of pregnancy. A growing body of evidence suggests an association between Hmox1 and angiogenesis, including placental angiogenesis. In this study, we examined the expression of two angiogenic factors in the placentas of Hmox1 deficient mouse embryos, whose expression was found to be related to that of Hmox1. Relative protein levels and localization of Hmoxs and two angiogenic factors [Vegf and Prolactin along with their receptors, and Cd31/Pecam1] were compared in the placentas of Hmox1 wildtype and knockout mouse embryos using western blotting and immunohistochemistry along with histological analysis. The results revealed tissue disorganisation, reduced area of labyrinth and smaller nuclear size of trophoblast giant cell in the placentas of knockout embryos. The levels of Hmox2, prolactin, and Cd31/Pecam1 were found to be altered in knockout placentas, whereas Vegf and its receptors seem to be unaltered in our samples. Overall, our findings imply that Hmox2 is unlikely to compensate for Hmox1 deficiency in knockout placentas, and altered levels of prolactin and Cd31/Pecam1 hint towards impaired angiogenesis in these placentas. Further investigation would be needed to understand the molecular mechanism of defective angiogenesis in the placentas of Hmox1 knockout mouse embryos.

Epigenetic Regulation of Angiogenesis in Peripheral Artery Disease.

Peripheral arterial disease (PAD) represents a global health concern with a rising prevalence attributed to factors such as obesity, diabetes, aging, and smoking. Among patients with PAD, chronic limb-threatening ischemia (CLTI) is the most severe manifestation, associated with substantial morbidity and mortality. While revascularization remains the primary therapy for CLTI, not all patients are candidates for such interventions, highlighting the need for alternative approaches. Impaired angiogenesis, the growth of new blood vessels, is a central feature of PAD, and despite decades of research, effective clinical treatments remain elusive. Epigenetics, the study of heritable changes in gene expression, has gained prominence in understanding PAD pathogenesis. Here, we explore the role of epigenetic regulation in angiogenesis within the context of PAD, with a focus on long non-coding RNAs and fibroblast-endothelial cell transdifferentiation. Additionally, we discuss the interplay between metabolic control and epigenetic regulation, providing insights into potential novel therapeutic avenues for improving PAD treatments. This review aims to offer a concise update on the application of epigenetics in angiogenesis and PAD research, inspiring further investigations in this promising field.