Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability

Abstract

Vascular permeability can be triggered by inflammation or ischemia in the heart, brain, or lung, where it promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability, and VEGF plays an integral role in regulating vascular barrier function in physiological conditions and a variety of pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis that often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue following pathological injury. Consequently, understanding the molecular mechanisms of VEGF-induced vascular permeability will facilitate the development of promising therapies that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair mediated by VEGF signaling. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that STAT3 ablation reduces vascular permeability using endothelial cell-specific STAT3 knockout mice as well as VEGF-inducible zebrafish crossed with CRISPR-Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in these animals. Wildtype C57BL/6 mice treated with JAK2 inhibitor, AG490, exhibit decreased vascular permeability when measured in vivo by Miles permeability assay, confirming the role of JAK2 in VEGF-induced vascular permeability. Using human endothelial cells, we describe a novel mechanism of STAT3-dependent transcriptional regulation of intercellular adhesion molecule 1 (ICAM-1), an endothelial transmembrane protein involved in the regulation of vascular permeability. FDA-approved anti-microbial drug, pyrimethamine (PYR), has been identified as an inhibitor of STAT3 function at concentrations known to be safely achieved in humans. We report that PYR substantially reduces VEGF-induced vascular permeability in mice. We confirm that pharmacologically targeting STAT3 increases vascular barrier integrity in human endothelium using two additional STAT3 inhibitor compounds, including atovaquone, an FDA-approved anti-parasitic drug shown to inhibit STAT3-dependent transcription. Taken together, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity and compounds known to inhibit STAT3-dependent activity reduce VEGF-induced vascular permeability in vertebrate models.

Transient leukocytopenia following combination therapy for COVID-19

“…The mechanism of transient leukocytopenia soon after combination therapy is unknown; however, considering that leukocytopenia occurred in a very short period, the temporally abnormal distribution of leukocytes may be a potential cause. Indeed, inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation reduces intracellular adhesion molecule 1 (ICAM1) expression [ 4 ], which may inhibit the adhesion of neutrophils to blood vessel walls and facilitate extravascular migration. Given that baricitinib is a reversible inhibitor of Janus kinase (JAK) 1/JAK2, which suppresses cytokine-induced phosphorylation of STAT3, baricitinib potentially induces short-term leukocyte depletion in blood, and thus, transient leukocytopenia.…”

Prognostic role of elevated VEGF in sepsis: A systematic review and meta-analysis

“…VEGF has important pro-angiogenic activity and participates in the regulation of normal and pathological angiogenesis (Melincovici et al, 2018). VEGF can induce leakage of blood vessels, and its increased expression can promote vascular hyperpermeability, edema and tissue damage (Wang et al, 2020). In sepsis, VEGF leads to vascular leakage and enhanced host response (Schuetz et al, 2011).…”

In silico analysis and preclinical findings uncover potential targets of anti-cervical carcinoma and COVID-19 in laminarin, a promising nutraceutical

“…In the pathway analysis, we found that laminarin's targets played a role in many cell signaling pathways related to COVID-19 and cervical carcinoma. The VEGF signaling pathway plays a vital role in the pathologies of COVID-19-associated pulmonary edema, sepsis, and acute lung injury (Wang et al, 2021). A clinical comparison study among the COVID-19 patient categories found a significantly lower level of VEGF in the mildly symptomatic patients (Tripathy et al, 2021).…”