Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy

Zhu, Weiquan; Shi, Dallas; Winter, Jacob M.; Rich, Bianca E.; Tong, Zongzhong; Sorensen, Lise K.; Zhao, Helong; Huang, Yi; Tai, Zhengfu; Mleynek, Tara; Yoo, Jae Hyuk; Dunn, Christine; Jing, Ling; Bergquist, Jake A; Richards, Jackson R.; Jiang, Amanda; Lesniewski, Lisa A.; Hartnett, M. Elizabeth; Ward, Diane M.; Mueller, Alan L.; Ostanin, Kirill; Thomas, Kirk R.; Odelberg, Shannon J.; Li, Dean Y.

doi:10.1172/jci91770

Cited by 42 publications

(65 citation statements)

References 40 publications

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“…Based on these data and previously published results (13–16), we propose a model of MDR GNB virulence that relies on LPS binding to TLR4, which activates two independent pathways that diverge at MyD88: 1) a pathway that activates a robust immune response via NF-κB, which is characterized by an increase in inflammatory cytokines; and 2) a pathway that compromises vascular integrity via activation of ARF6 and internalization of VE-cadherin, resulting in excessive vascular leak, tissue edema, organ failure, and death. ARF6 inhibitors block vascular leak without affecting the LPS-induced inflammatory immune response, thereby allowing the immune system to fight the infection (Figure 7).…”

Section: Resultssupporting

confidence: 67%

“…Small molecule ARF6 inhibitors, NAV-2729, A6-4424, and A6-5093 were evaluated for efficacy in treating murine pneumonia due to GNB. NAV-2729 (IC50 = 1.5 μM) has been shown to have therapeutic benefit in alleviating animal models of diabetic retinopathy (16). A6-5093 is a new highly soluble prodrug of A6-4424 designed to enhance in vivo administration.…”

Section: Resultsmentioning

confidence: 99%

“…ARF6 activation leads to increased vascular permeability via internalization of the adherens junction protein VE-cadherin (13, 15, 16). Thus, we hypothesized that ARF6 inhibitors protect mice from GNB infection by maintaining vascular integrity.…”

Section: Resultsmentioning

confidence: 99%

“…Stabilizing the vasculature to prevent fluid leak, without compromising the beneficial innate immune system response, may allow the host ample time to clear the infection without causing organ failure. The activation state of ARF6, which is a convergence point in the signaling pathways of several inflammatory mediators and cytokines, plays a major role in controlling vascular permeability (13–16). When ARF6 is in its activated GTP-bound state, permeability is increased, and when it is in its inactive GDP-bound state, the vasculature is stabilized leading to decreased permeability.…”

Section: Introductionmentioning

confidence: 99%

“…Proinflammatory agonists such as IL-1β, GNB lipopolysaccharides (LPS), and vascular endothelial growth factor (VEGF) activate ARF6, which in turn promotes the internalization of the adherens junction protein VE-cadherin and thereby increases endothelial permeability (13, 15, 16). We have shown that stabilizing the vasculature by reducing ARF6 activity is an effective strategy for reversing pathology and increasing survival rates in several preclinical models of inflammatory and vascular disease, including arthritis (15), LPS-induced endotoxemia (13), and diabetic retinopathy (16). Here, we show that stabilizing the vasculature through pharmacological inhibition of ARF6 activation by small molecules can increase survival rates and reduce pathology in preclinical models of MDR GNB infections.…”

Section: Introductionmentioning

confidence: 99%

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Preserving Vascular Integrity Protects Mice Against Multidrug-Resistant Gram-Negative Bacterial Infection

Gebremariam¹,

Zhang

Alkhazraji³

et al. 2020

Preprint

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ABSTRACTThe rise in multidrug resistant (MDR) organisms portends a serious global threat to the healthcare system with nearly untreatable infectious diseases, including pneumonia and its often fatal sequelae, acute respiratory distress syndrome (ARDS) and sepsis. Gram-negative bacteria (GNB) including Acinetobacter baumannii, Pseudomonas aeruginosa, and carbapenemase-producing Klebsiella pneumoniae (CPKP), are among the World Health Organization and National Institutes of Health’s high priority MDR pathogens for targeted development of new therapies. Here we show that stabilizing the host’s vasculature by genetic deletion or pharmacological inhibition of the small GTPase ADP-ribosylation factor 6 (ARF6) increases survival rates of mice infected with A. baumannii, P. aeruginosa, CPKP pneumonia. We show that pharmacological inhibition of ARF6-GTP phenocopies endothelial-specific Arf6 disruption in enhancing survival of mice with A. baumannii pneumonia, suggesting that inhibition is on target. Finally, we show that the mechanism of protection elicited by these small molecule inhibitors is by restoration of vascular integrity disrupted by GNB lipopolysaccharide (LPS) activation of TLR4/MyD88/ARNO/ARF6 pathway. By targeting the host’s vasculature with small molecule inhibitors of ARF6 activation, we circumvent microbial drug resistance and provide a potential alternative/adjunctive treatment for emerging and re-emerging pathogens.

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Preserving Vascular Integrity Protects Mice Against Multidrug-Resistant Gram-Negative Bacterial Infection

Gebremariam¹,

Zhang

Alkhazraji³

et al. 2020

Preprint

Self Cite

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Cu‐Doping Layered Double Hydroxides Nanozyme Integrated with Nitric Oxide Donor for Enhanced Antioxidant Therapy in Retinopathy

Xue,

Lu,

Wang

et al. 2024

Adv Healthcare Materials

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The prevalence of retinal neovascular diseases necessitates novel treatments beyond current therapies like laser surgery or anti‐VEGF treatments, which often carry significant side effects. A novel therapeutic approach is introduced using copper‐containing layered double hydroxides (Cu‐LDH) nanozymes integrated with nitric oxide‐releasing molecules (GSHNO), forming Cu‐LDH@GSHNO aimed at combating oxidative stress within the retinal vascular system. Combination of synthetic chemistry and biological testing, Cu‐LDH@GSHNO are synthesized, characterized, and assessed for curative effect in HUVECs and an oxygen‐induced retinopathy (OIR) mouse model. The results indicate that Cu‐LDH@GSHNO demonstrates SOD‐CAT cascade catalytic ability, accompanied with GSH and nitric oxide‐releasing capabilities, which significantly reduces oxidative cell damage and restores vascular function, presenting a dual‐function strategy that enhances treatment efficacy and safety for retinal vascular diseases. The findings encourage further development and clinical exploration of nanozyme‐based therapies, promising a new horizon in therapeutic approaches for managing retinal diseases driven by oxidative stress.

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KIF13B mediates VEGFR2 recycling to modulate vascular permeability

Cho

Nhàn

Zhou

et al. 2023

Cell. Mol. Life Sci.

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Excessive vascular endothelial growth factor-A (VEGF-A) signaling induces vascular leakage and angiogenesis in diseases. VEGFR2 tra cking to the cell surface, mediated by kinesin-3 family protein KIF13B, is essential to respond to VEGF-A in inducing angiogenesis. However, the precise mechanism of how KIF13B regulates VEGF-induced signaling and endothelial permeability is unknown. Here we show that KIF13B-mediated recycling of internalized VEGFR2 through Rab11-positive recycling vesicle regulates VE-cadherin phosphorylation and endothelial permeability. Phosphorylated VEGFR2 at the cellcell junction was internalized and associated with KIF13B in Rab5-positive early endosomes. KIF13B mediated VEGFR2 recycling through Rab11-positive recycling vesicle, and inhibition of this recycling attenuated phosphorylation of VEGFR2 at Y951, Src, and VE-cadherin at Y685, which are necessary for endothelial permeability. Failure of VEGFR2 tra cking to the cell surface induced accumulation and degradation of VEGFR2 in lysosomes. Furthermore, in the animal model of wet age-related macular degeneration (AMD), inhibition of KIF13B-mediated VEGFR2 tra cking also mitigated vascular leakage. Thus, the present results identify the fundamental role of VEGFR2 recycling to the cell surface in mediating vascular permeability, suggesting a promising strategy for mitigating vascular leakage associated with in ammatory diseases.

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Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy

Cited by 42 publications

References 40 publications

Preserving Vascular Integrity Protects Mice Against Multidrug-Resistant Gram-Negative Bacterial Infection

Preserving Vascular Integrity Protects Mice Against Multidrug-Resistant Gram-Negative Bacterial Infection

Cu‐Doping Layered Double Hydroxides Nanozyme Integrated with Nitric Oxide Donor for Enhanced Antioxidant Therapy in Retinopathy

KIF13B mediates VEGFR2 recycling to modulate vascular permeability

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