Vascular Endothelial Growth Factor as an Immediate-Early Activator of UV-induced Skin Injury

Abstract

The negative health consequences of acute ultraviolet (UV) exposure are evident, with reports of 30,000 emergency room visits annually to treat the effects of sunburn in the United States alone. The acute effects of sunburn include erythema, edema, severe pain, and chronic overexposure to UV radiation, leading to skin cancer. While the pain associated with the acute effects of sunburn may be relieved by current interventions, existing post-sunburn treatments are not capable of reversing the cumulative and long-term pathological effects of UV exposure, an unmet clinical need. Here we show that activation of the vascular endothelial growth factor (VEGF) pathway is a direct and immediate consequence of acute UV exposure, and activation of VEGF signaling is necessary for initiating the acute pathological effects of sunburn. In UV-exposed human subjects, VEGF signaling is activated within hours. Topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small-molecule antagonists of VEGF receptor signaling, prevent the development of erythema and edema in UV-exposed mice. These findings collectively suggest targeting VEGF signaling may reduce the subsequent inflammation and pathology associated with UV-induced skin damage, revealing a new post-exposure therapeutic window to potentially inhibit the known detrimental effects of UV on human skin. It is essential to emphasize that these preclinical studies must not be construed as suggesting in any way the use of VEGF inhibitors as a sunburn treatment in humans because warranted future clinical studies and appropriate agency approval are essential in that regard.

Skin is our largest organ and is critical for exposure to the environment and social interaction. Ultraviolet (UV) radiation from the sun elicits dramatic acute and chronic effects. Approximately 30,000 Americans are admitted to the emergency room annually to treat the effects of sunburn, including erythema, edema, and severe pain¹. Chronic UV exposure induces decreased skin elasticity, promotes increased wrinkling^{2, 3}, and is associated with skin cancers^{4, 5}. A history of severe sunburns has been associated with increased risks for all types of skin cancer, including melanoma, squamous cell carcinoma, and basal cell carcinoma⁶. While the increasing incidence of these three types of skin cancer has resulted in a greater focus on sun exposure habits⁷, one-third of Americans report experiencing sunburn within the past year⁸. In a recent study of over 4,000 Americans, most individuals reported that during their most recent sunburn, they were using a form of sun protection, including sunscreen on the face, neck, and chest (38.8% of participants), sunscreen on the body (19.9%), wearing sunglasses (34.2%), wearing a baseball cap or visor (15.7%), staying in the shade (15.4%), wearing a wide-brimmed hat (12.3%), wearing clothes to the ankles (6.6%), or wearing a long-sleeved shirt (4.5%)⁹. Participants in this US-based survey reported that sunburns most frequently occurred while swimming or spending time in water (32.5%), working outdoors at home (26.2%), traveling or vacationing (20.7%), and performing non-swimming physical activity (14.2%)⁹. While the risk of sunburns can be minimized by using various forms of sun protection, this study’s findings highlight the challenges associated with sunburn prevention, such as the need to reapply sunscreen during outdoor aquatic activities or the relatively low usage of pants and long-sleeved shirts for sun protection. Indeed, nearly 80% of participants recollected using at least one form of sun protection during the occurrence of their most recent sunburn⁹. Current sunburn treatments, such as non-steroidal anti-inflammatory medications, aloe vera gels, and systemic and topical corticosteroids, may provide immediate pain relief but do not reverse the cumulative and chronic pathological effects of UV exposure¹⁰. Thus, viable post-exposure sunburn treatments represent an unmet clinical need.

In addition to DNA damage¹¹, UV exposure causes immunomodulation through multiple molecular mechanisms in innate and adaptive immune systems. Acute inflammation is a well-established hallmark of the human body’s response to sunburn¹². However, the immediate pathological effects of sunburn (i.e., pain, itching, swelling, redness, and skin that feels hot to the touch) can occur hours before the acute inflammatory response. Angiogenesis, the process of new blood vessel formation from pre-existing vessels, has been implicated in the initial skin response to UV exposure^{13, 14}. Angiogenesis is characterized by the migration and proliferation of vascular endothelial cells and increased microvascular permeability. Vascular endothelial growth factor (VEGF) was initially discovered as "vascular permeability factor" (VPF), a tumor secreted factor that strongly promotes vascular permeability¹⁵, and subsequently identified as VEGF, an endothelial mitogen essential for the development of blood vessels¹⁶. VEGF is upregulated following UV exposure in mice, and increased VEGF causes sensitization to UV and increased severity of sunburn, including greater vascularity and edema^{13, 14}. However, the importance of VEGF activation in response to acute UV-induced skin damage remains underappreciated.

The VEGF family of proteins includes VEGF-A, VEGF-B, VEGF-C, VEGF-D, placenta growth factor (PlGF), parapoxvirus VEGF-E, and snake venom VEGF-F. VEGF ligands bind with high affinity to the receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, which exhibit differences in their mode of activation, signal transduction, and downstream functional consequences¹⁷. VEGFR-2 is the primary receptor in blood endothelium and signals to mediate endothelial cell permeability, proliferation, survival, and migration^{18, 19}. Given that VEGF-A is the primary isoform involved in regulating angiogenesis via its interaction with VEGFR-2, VEGF-A will be referred to as "VEGF" henceforth as the focus of this overview. VEGF also binds to co-receptors, such as neuropilin-1, -2, and heparan sulfate proteoglycans^20–25, to form complexes consisting of receptors, co-receptors, and non-VEGF binding adaptors, like integrins and ephrin B2²⁶. VEGF binding to a VEGFR results in receptor dimerization, stimulation of tyrosine kinase activity, and autophosphorylation of intracellular tyrosine residues²⁷. These VEGFR phosphotyrosines serve as docking sites for adaptor molecules that initiate various signaling pathways to regulate angiogenesis¹⁷ (Figure 1).

Figure 1: UVB radiation activates VEGF-A/VEGFR-2 signaling in endothelial cells and lymphocytes to regulate cellular functions.

UVB radiation causes increased production of VEGF-A, which binds to VEGFR-2 expressed on the surface of endothelial cells and immune cells. VEGF-A, a member of a family of proteins including VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and PlGF, binds VEGFR-2 and various co-receptors to activate downstream signal transduction pathways that regulate survival, migration, and permeability in endothelial cells. In lymphocytes, VEGF/VEGFR-2 interactions stimulate T-cell activation and a shift towards a Th1 phenotype along with upregulation of IL-6 and TNF-alpha in PBMCs. VEGF-A also interacts with VEGFR-1 and VEGFR-3 to promote vasculogenesis and lymphangiogenesis, respectively. VEGF-A, vascular endothelial growth factor A; VEGFR-2, vascular endothelial growth factor receptor 2; PlGF, placental growth factor; Th1, Type 1 T helper; IL-6, interleukin 6; TNF-alpha, tumor necrosis factor alpha; PBMCs, peripheral blood mononuclear cells.

We hypothesize that activation of the VEGF pathway is a direct and immediate consequence of acute UV exposure and is essential for initiating the pathological effects of sun exposure in the epidermis. Supporting evidence suggests that UV induces VEGF and VEGFR-2 upregulation and that upregulation of VEGF sensitizes the skin to UV and increased sunburn severity. Therefore, we reason that VEGF signaling inhibition may prevent or reduce the pathological consequences of UV-induced skin damage, including the development of erythema and edema associated with acute sunburn. Acute UVB-induced edema, erythema, and increased vascularity can be substantially reduced by disrupting VEGF signaling via systemic or topical anti-VEGF antibody administration.

Antibody-mediated suppression of VEGF signaling can be enhanced by gold nanoparticles, which possess intrinsic antiangiogenic properties due to selective inhibitory interactions with heparin-binding growth factors, such as VEGF and bFGF²⁸. Nanoparticles represent an emerging type of broadly applicable nanotechnology, defined as nanometer-scale materials (0.1–100 nm) composed of a basic unit approximately equivalent to the size of 10–100 atoms arranged closely together^{29, 30}. As early as 1857, Faraday reported the light scattering potential of gold nanoparticles, characterized by the change of red color and colloidal properties of nanomaterials³¹. More recently, metal nanoparticles have been used for various medical applications, including drug and gene delivery, radiation therapy, diagnostics, and radiology³². Inparticular, gold nanoparticles boost strong biocompatibility, very high surface area amenable to loading large amounts of conjugates, straightforward characterization, and easy surface modification to enable attachment of drugs, peptides, and antibodies^{28, 32, 33}. Here, we utilize gold nanoparticles conjugated to anti-VEGF antibodies to enhance VEGF signaling inhibition and amplify the associated reduction of angiogenesis. We have previously demonstrated potential therapeutic applications of this approach by enhancing anti-VEGF antibody-mediated apoptosis of B-Chronic Lymphocytic Leukemia (CLL) cells by treating CLL B cells with gold nanoparticles attached to anti-VEGF antibodies, which exhibited increased cellular cytotoxicity relative to antibody or gold nanoparticles administered alone separately³⁴.

Here, we tested the hypothesis that activation of the VEGF pathway is a direct and immediate consequence of acute UV exposure and is essential for initiating the pathological effects of sun exposure in the epidermis. We propose that VEGF induction causes edema and the related immediate impact on the skin while working concomitantly with reactive oxygen species (ROS) to induce inflammation. Specifically, we show that VEGF signaling is activated within hours of solar simulated light exposure in human subjects. Using a mouse post-UV exposure model, we show that topical delivery of VEGF pathway inhibitors, targeted against the ligand VEGF-A (gold nanoparticles conjugated with anti-VEGF antibodies) and small-molecule antagonists of VEGF receptor signaling, can dramatically prevent the subsequent development of erythema and edema associated with acute sunburn. Together, these results demonstrate a novel and clinically relevant method of skin injury treatment following UV exposure, highlighting the understudied role of the VEGF/VPF pathway in both acute and chronic sun damage.

METHODS:

Mice:

Six- to eight-week-old female SKH1-Elite hairless mice were purchased (Stain Code: 477, Charles River). All mice were housed in a temperature-controlled room with alternating 12 h light/dark cycles, allowed one week to acclimate to their surroundings, and fed a standard diet. All animal work was conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, and all animal protocols were approved by the Institutional Animal Care and Use Committee at Mayo Clinic and the University of Minnesota.

UV Irradiation Studies:

Six- to eight-week-old female SKH1-Elite hairless mice were exposed to graded doses of a single UVB irradiation using fluorescent lamps. The height of the lamps was adjusted to deliver 0.82 mW/cm² at the dorsal skin surface. The minimal erythema dose (MED) was determined by irradiation of eight 1 cm² areas on the skin on the front of mice with seven graded doses of UVB irradiation ranging from 0.056 J/cm² to 0.4 J/cm² as well as sham irradiation. Erythema formation was evaluated after 48 hours by two independent observers. To determine the systemic effect of VEGF inhibition on acute UVB skin injury, mice were treated with 50 μg VEGF-neutralizing antibody 2C3 by intraperitoneal injection 24 hours before exposure 0.144 J/cm² of UVB radiation to the ears. The extent of ear edema was determined by measuring ear thickness as previously described¹³. Samples of dorsal skin and ears were snap-frozen in liquid nitrogen or fixed in formaldehyde. To evaluate topical treatment effectiveness on acute UVB exposure, ears of six- to eight-week-old female C57BL/6 (n=5 per group) were exposed to one dose of 0.144 J/cm² UVB radiation. Topical treatments (25 ug/mice mixed in 1 mL of Vanicream) or control vehicle (Vanicream) were applied two hours post-radiation. The extent of ear edema was determined by measuring the change in ear thickness 48 hours post-radiation. Samples of ears were snap-frozen in liquid nitrogen or fixed in formaldehyde. All mice were administered carprofen via their drinking water 48 hours before UV exposure to reduce pain from the UV-induced skin damage.

Preparation of gold-nanoparticle antibody cream:

Vanicream (Pharmaceutical Specialties, Inc.) was mixed with an equal GNP-antibody conjugate volume. The typical dose of GNP-antibody administered topically to each mouse was 25 μg unless indicated otherwise. VEGF neutralizing antibodies used were 2C3 (Peregrine Pharmaceuticals) and bevacizumab (Avastin®, Genentech).

Gold-nanoparticle antibody conjugation:

Naked gold nanoparticles (GNPs) were synthesized by adding 500 ml of an aqueous solution containing 43 mg of sodium borohydride (Sigma Aldrich) to 1000 ml of 0.1 mM HAuCl4 (Sigma Aldrich) solution under constant stirring, overnight at room temperature. The desired antibody (800 μg of 2C3, Avastin, or IgG) was suspended in 1 ml of molecular biology grade water and added dropwise to 200 ml of naked GNP solution under constant stirring at ambient temperature for two hours. The mixture was centrifuged at 22,000 rpm in a Beckman Coulter ultracentrifuge at 4°C for 65 minutes twice to separate the GNP-antibody conjugate from naked antibody. The supernatant was removed, and the conjugated GNP-antibody pellet was suspended in molecular biology grade water to the desired concentration.

Quantitative PCR Analysis:

Purified RNA was isolated from mouse skin using the RNeasy Plus Mini Kit (Qiagen) after pulverizing the frozen skin tissue and homogenization with the QIAshredder system (Qiagen). Quantitative PCR was performed using the QuantiTech SYBR Green RT-PCR kit (Qiagen) per the manufacturer’s instructions. Briefly, RNA (50 ng) was added to 30 μl reactions with QuantiTech SYBR Green RT master mix, QuantiTech RT mix, and 0.5 pmol/μl of each of the oligonucleotide primers.

Total RNA was isolated from frozen mouse skin tissues using the RNeasy Plus kit (Qiagen) according to the manufacturer’s instructions. Mice skin tissues chopped with a sterile scalpel were lysed and homogenized with the QIAshredder system (Qiagen). Isolated RNA (50 ng) was subjected to qRT-PCR analysis using iTaq™ Universal SYBR® Green One-Step Kit (Bio-Rad) in the 7500 Real-Time PCR System (Applied Biosystems). The comparative threshold cycle method (ΔΔCt) was used to quantify relative amounts of murine VEGF-A transcripts. Mouse GAPDH gene acts as an endogenous reference control. Primer sequences (forward and reverse, respectively) used for qRT-PCR were as follows. VEGFA: 5’-CAGGCTGCTGTAACGATGAA-3’ and 5’-TCACCGCCTTGGCTTGTCAC-3’; GAPDH: 5’-AACTTTGGCATTGTGGAAGG-3’ and 5’-ACACATTGGGGGTAGGAACA-3’.

Immunohistochemistry staining:

Human skin tissue specimens were collected from each of four human subjects at 5 minutes, 1 hour, 5 hours, and 24 hours post-exposure to 2.5 MED solar-simulated UV light at the University of Arizona in accordance with Institutional Review Board approval and informed written consent of all study participants³⁵. Formalin-fixed, paraffin-embedded, serially sectioned specimens mounted on glass slides were a generous gift from Dr. Clara Curiel-Lewandrowski at the University of Arizona. Slides were immunostained using antibodies that recognize total VEGFR-2 (#2479, Cell Signaling Technology) and phosphorylation of VEGFR-2 at Y1175 (#2478, Cell Signaling Technology) as previously described³⁶. Pathological review and analysis of the immunostaining were performed by a board-certified pathologist (D.M.S.) at the University of Minnesota, and histological findings have been reported in Figure 2 and Supplementary Table 1.

Figure 2: UV exposure activates VEGF signaling in human subjects.

Skin tissue specimens collected from human subjects (n=4) at 5 minutes, 1 hour, 5 hours, and 24 hours post-exposure to 2.5 MED solar-simulated UV light were immunostained using antibodies that detect total VEGFR-2 protein (left column) and VEGFR-2 phosphorylated at its Y1175 residue (p-VEGFR-2; right column). Representative images are shown. Scale bar indicates 20 μm. VEGF, vascular endothelial growth factor; VEGFR-2, vascular endothelial growth factor receptor 2; MED, minimal erythema dose.

Tissue was harvested from the ears of mice exposed to a single 1.0 MED UVB exposure of 0.144 J/cm², preceded by intraperitoneal injection with 50 μg VEGF-neutralizing antibody 2C3 or negative control PBS 24 hours before UVB exposure. Formalin-fixed, paraffin-embedded, serially sectioned specimens mounted on glass slides were immunostained using a polyclonal CD31 antibody (sc-1506, Santa Cruz Biotechnology). Following analysis of the immunostaining, representative histological images have been reported in Supplementary Figure 1.

Statistical analysis:

Statistical comparisons were performed with one-way analysis of variance (ANOVA) using GraphPad Prism 8 software. Differences between groups were considered significant when values of P≤0.05. Dunnett multiple comparison tests were performed in all applicable experiments after one-way ANOVA to make comparisons between groups. Data are expressed as mean ± SEM and representative of at least two independent experiments.

RESULTS:

We assessed whether activation of the VEGF pathway is a direct and immediate consequence of acute UV exposure in human subjects exposed to solar simulated UV light. We performed immunostaining for total VEGFR-2 protein and phosphorylation of VEGFR-2 at Y1175 (pVEGFR-2) using skin tissue specimens obtained from four human subjects exposed to a 2.5 minimal erythema dose (MED) of solar-simulated UV light (Figure 2). We observed virtually undetectable pVEGFR-2 immunostaining at 0, 5, and 60 minutes following UV exposure. At 5 hours post-UV exposure, mild to moderate pVEGFR-2 was observed within the stratum basale of the epidermis. By 24 hours post-UV exposure, similar pVEGFR-2 was also detectable but at a lesser frequency (Figure 2, Supplementary Table 1). Strong total VEGFR-2 staining was present within the dermis of human skin at all time points, while greater epidermal total VEGFR-2 expression positively correlated with increased duration of solar-simulated UV exposure (Figure 2, Supplementary Table 1). Together, these results suggest VEGF signaling is activated within 5 hours of UV exposure in humans.

Exposure to ultraviolet B (UVB) irradiation induces skin alterations such as erythema, dilation of dermal blood vessels, vascular hyper-permeability, and epidermal hyperplasia, which comprises acute photodamage. To determine the minimal erythema dose (MED) required to induce these pathological features of acute skin damage, various UVB doses were applied to flank skin of immunocompetent, hairless SKH1 mice. Erythema was observed in mice by 48 hours, following exposure to 0.144 J/cm² or greater UVB. We performed qPCR to determine VEGF expression level using mRNA derived from mice 48 hours after exposure to various doses of UVB. We observed dose-dependent increases in the skin starting at 0.144 J/cm² UVB (Figure 3A).

Figure 3: Topical inhibition of VEGF signaling reduces UV-induced skin damage in mice.

(a) Quantitative PCR was used to measure induction of VEGF transcript in mouse skin at 48 hours post-exposure to various indicated doses of UVB (n=3 mice). (b, c) Ears of mice (2 separate experiments, n=4 mice per group) were exposed to a single 1.0 MED UVB exposure of 0.144 J/cm² after treatment with 50 μg VEGF-neutralizing antibody 2C3 or negative control PBS by intraperitoneal injection 24 hours prior. Representative images are shown (b). Extent of ear edema was determined by measuring ear thickness 48 hours post radiation. (c). (d) Ears of mice (n=5 mice per group) were exposed once to 1.0 MED of UVB radiation at 0.144 J/cm². Indicated topical treatments (25 μg per mouse; 12.5 μg per ear) or control vehicle (Vanicream) were applied two hours post-radiation. Extent of ear edema was determined by measuring the change in ear thickness 48 hours post-radiation. (e, f) Topical administration of GNP-VEGF antibody (25 ug per mouse; 12.5 μg per ear) or small molecule inhibitor of VEGF signaling, sorafenib (25 ug per mouse; 12.5 μg per ear) reduces edema (2 separate experiments, n=5 mice per group). All treatments were applied 2 hours following 1.0 MED UVB exposure of 0.144 J/cm2 UVB. Ear thickness was measured 2 days after UVB exposure. Quantitative PCR was used to measure induction of VEGF transcript in mouse ear skin following UV exposure and treatment in a subset of mice (f). VEGF, vascular endothelial growth factor; MED, minimal erythema dose; PBS, phosphate buffered saline; GNP, gold nanoparticles.

To determine whether VEGF induction is necessary for acute photodamage development, we treated mice with an intraperitoneal injection of 50 μg VEGF antibody 2C3 and exposed their ears to 1.0 MED. Along with erythema and increased vascularity, UVB-exposed, untreated mice showed signs of edema as evidenced by increased ear thickness. Intraperitoneal administration of 2C3 decreases blood vessel dilation (Figure 3B), reduces edema as shown by 50% decrease in ear thickness (Figure 3C), and reduces angiogenesis as shown by decreased CD31-positive endothelial cells in UVB-exposed mouse ears (Supplemental Figure 1). These findings suggest that VEGF is induced early and necessary for the development of acute photodamage.

We investigated the efficacy of topical administration of GNP-conjugated VEGF antibody in preventing acute photodamage after UVB exposure. As we intended this as a treatment instead of prophylactic measures, we applied the topical treatment 2 hours after exposing healthy mice ears to UVB. We showed that topical GNP conjugated to two different VEGF antibodies (2C3 or Avastin) is superior in reducing edema compared to topical VEGF antibody or GNP alone (Figure 3D). Topical administration of sorafenib, a small molecule VEGFR-2 tyrosine kinase inhibitor, similarly reduced mouse-ear thickness caused by UVB exposure (Figure 3E). Quantitative PCR of skin tissue RNA confirmed that topical administration of sorafenib or GNP conjugated VEGF antibody reduced VEGF transcript levels in UVB exposed mice (Figure 3F). These results suggest topical inhibition of VEGF signaling after UVB exposure effectively prevents the development of acute photodamage. To our knowledge, this is the first study demonstrating that acute UVB-induced skin injury can be prevented following exposure.

DISCUSSION:

Solar UV radiation is subdivided into three categories, UVA, UVB, and UVC37. Most UVB rays penetrate the epidermis or upper region of the dermis³⁸. UVB light is 1,000–10,000 times more carcinogenic than UVA radiation measured by DNA damage and erythema³⁹. Our studies focus on the molecular initiation of UVB induced skin damage and its associated pathology and suggest that topical inhibition of VEGF/VPF signaling reduces photodamage in vivo, which occurs well before activating the innate immune response.

We propose that early activation of VEGF signaling is a direct and immediate response to acute UVB exposure that leads to edema and related pathological effects on the skin. We demonstrate through immunostaining that VEGFR-2 activation via phosphorylation of the Y1175 residue in the epidermis of human subjects exposed to solar-simulated UV rays peaks at 5 hours post-exposure. Reverse-phase protein arrays using similar human specimens suggested that VEGFR-2 Y996 was increased at 1 hour and 5 hours post-UV exposure ³⁵. While the functional consequences of VEGFR-2 Y996 are unknown, this residue serves as a docking site for SH2, SH3, or PTB domain-containing proteins to convey downstream signaling^{17, 40}. VEGFR-2 Y1175 phosphorylation stimulates the PLCγ-ERK1/2 cascade, regulates Ca2+ signaling, and cell survival and proliferation ⁴¹. Human keratinocytes and epidermis express VEGF receptors and co-receptors, and autocrine VEGF/VEGFR-2 signaling is activated in response to moderate UVB irradiation^{42, 43}. VEGF is produced through distinct mechanisms by UVB and ROS⁴⁴, as UVB has been shown to activate VEGF in the presence of antioxidants ⁴⁵. UVB and inflammatory mediator PGE2 directly upregulate VEGF in human dermal fibroblasts and indirectly elevate VEGF in human epidermal keratinocytes⁴⁶. Potentiation of the VEGF/VEGFR-2-mediated angiogenic response induced by UVB in VEGF transgenic mice stimulated UV-induced cutaneous skin damage yet did not contribute to wound healing and repair mechanisms¹³.

We show that VEGF-A is induced immediately following acute UVB exposure in mice. The acute UVB-induced edema, erythema, and increased vascularity can be substantially reduced by disrupting VEGF signaling via systemic or topical anti-VEGF antibody administration. GNPs possess intrinsic antiangiogenic properties due to selective inhibitory interactions with heparin-binding growth factors, such as VEGF and bFGF²⁸. Indeed, topical application of GNP conjugated to VEGF antibody synergistically reduces acute UVB-induced edema in mice. This is supported by studies demonstrating that UVB irradiation induces an angiogenic switch mediated by upregulation of VEGF and that elevation of VEGF increases photosensitivity^{13, 14, 47}. This effect is mediated through activation of VEGFR-2 as topical administration of sorafenib produces similar improvement. VEGF/VEGFR-2 transduces signals through JAK/STAT proteins⁴⁸, and inhibition of JAK2/STAT3-dependent autophagy with Sanshool exhibited a photoprotective effect in human dermal fibroblasts and hairless mice exposed to UVB irradiation⁴⁹.

CONCLUSION:

Our findings suggest VEGF/VPF signaling is an immediate-early activator of UV-induced skin injury and plays an integral role in the associated pathology, which occurs well before the innate immune response. Thus, targeting VEGF/VEGFR-2 signaling reduces the subsequent inflammation and pathology associated with UV-induced skin damage. It is essential to emphasize that these preclinical studies must not be construed as suggesting in any way the use of VEGF inhibitors as a sunburn treatment in humans because warranted future clinical studies and appropriate agency approval are essential in that regard.

ABBREVIATIONS:

UV

Ultraviolet radiation

UVB

Ultraviolet B

VEGF

Vascular endothelial growth factor

VPF

Vascular permeability factor

ROS

Reactive oxygen species

MED

Minimal erythema dose

GNP

Gold nanoparticle

Data Availability Statement:

Data about this study are included in the manuscript and supplementary information. All datasets are freely available upon request to the corresponding authors.