Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia.

[Figure: see text].

Vascular endothelial growth factor B exerts lipid-lowering effect by activating AMPK via VEGFR1.

As an ambiguous member of vascular endothelial growth factor family, VEGF-B has long been poorly understood in its function. Recent researches showed VEGF-B isoforms exerted their metabolic effect through indirectly activating the VEGF-A/VEGFR2 pathway. Here, we report the lipid-lowing effect of VEGF-B via VEGFR1. We investigated the effect of VEGF-B on lipid metabolism in vivo and in vitro approaches. Treatment of mice with VEGF-B recombinant protein repressed HFD-induced body weight gain. This treatment also alleviated obesity associated hyperlipidemia and fatty liver disease. In the muscle and liver of VEGF-B-treated HFD mice were observed increased protein expression of carnitine palmitoyltransferase-1 (CPT-1) and the phosphorylation of ACC and AMP-activated protein kinase (AMPK). This effect was confirmed in HepG2 cells incubated with VEFG-B in which the increased AMPK activation and CPT-1 expression occurs due to activation of Calcium/calmodulin-dependent Protein Kinase ß (CaMKKß) by VEFG-B. VEGF-B increased expression of key genes responsible for lipid oxidation while reducing those for fatty acid synthesis in vivo and in vitro. In addition, the selective inhibitor of VEGFR1 blocked the lipid clearance effect of VEGF-B in HepG2. Our study unraveled unknown role of VEGF-B/VEGFR1 signaling in regulating lipid metabolism. Furthermore, our findings indicate that VEGF-B may have beneficial effects for the treatment of dyslipidemia.

Improving high-fat diet-induced obesity and fatty liver by adipose tissue targeted delivery of vascular endothelial growth factor-B.

Impaired vascularization of adipose tissue leads to local hypoxia and results in chronic inflammation and obesity-related metabolic disorders. We have recently constructed an engineered protein named tPep-VEGF-B by bridging vascular endothelial growth factor (VEGF-B) with an adipose-targeted peptide. Here, we reported tPep-VEGF-B diminishes obesity and alleviates metabolic syndrome. High fat diet (HFD) treated mice had reduced adipose vascular density and showed adipose hypoxia and metabolic complications. In contrast, the treatment of tPep-VEGF-B repressed HFD-induced body weight gain, which led to increased adipose vasculature and reduced hypoxia. This treatment also alleviated obesity associated hyperlipidemia and fatty liver disease. This study provided a leading molecule for the treatment of type 2 diabetes and other metabolic diseases. It also provided experimental support for the theory that modulation of angiogenesis plays a key role in the treatment of metabolic diseases.

VEGF-B inhibits hyperglycemia- and Macugen-induced retinal apoptosis.

Vascular endothelial growth factor B (VEGF-B) was discovered a long time ago. However, its role in hyperglycemia- and VEGF-A inhibition-induced retinal apoptosis remains unknown thus far. Yet, drugs that can block VEGF-B are being used to treat patients with diabetic retinopathy and other ocular neovascular diseases. It is therefore urgent to have a better understanding of the function of VEGF-B in these pathologies. Here, we report that both streptozotocin (STZ)-induced diabetes in rats and Macugen intravitreal injection in mice leads to retinal apoptosis in retinal ganglion cell and outer nuclear layers respectively. Importantly, VEGF-B treatment by intravitreal injection markedly reduced retinal apoptosis in both models. We further reveal that VEGF-B and its receptors, vascular endothelial growth factor 1 (VEGFR1) and neuropilin 1 (NP1), are abundantly expressed in rat retinae and choroids and are upregulated by high glucose with concomitant activation of Akt and Erk. These data highlight an important function of VEGF-B in protecting retinal cells from apoptosis induced by hyperglycemia and VEGF-A inhibition. VEGF-B may therefore have a therapeutic potential in treating various retinal degenerative diseases, and modulation of VEGF-B activity in the eye needs careful consideration.

VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism and serves as a marker of poor prognosis for cancer patients.

The biological functions of VEGF-B in cancer progression remain poorly understood. Here, we report that VEGF-B promotes cancer metastasis through the remodeling of tumor microvasculature. Knockdown of VEGF-B in tumors resulted in increased perivascular cell coverage and impaired pulmonary metastasis of human melanomas. In contrast, the gain of VEGF-B function in tumors led to pseudonormalized tumor vasculatures that were highly leaky and poorly perfused. Tumors expressing high levels of VEGF-B were more metastatic, although primary tumor growth was largely impaired. Similarly, VEGF-B in a VEGF-A-null tumor resulted in attenuated primary tumor growth but substantial pulmonary metastases. VEGF-B also led to highly metastatic phenotypes in Vegfr1 tk(-/-) mice and mice treated with anti-VEGF-A. These data indicate that VEGF-B promotes cancer metastasis through a VEGF-A-independent mechanism. High expression levels of VEGF-B in two large-cohort studies of human patients with lung squamous cell carcinoma and melanoma correlated with poor survival. Taken together, our findings demonstrate that VEGF-B is a vascular remodeling factor promoting cancer metastasis and that targeting VEGF-B may be an important therapeutic approach for cancer metastasis.

Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms.

BACKGROUND: New revascularization therapies are urgently needed for patients with severe coronary heart disease who lack conventional treatment options. METHODS AND RESULTS: We describe a new proangiogenic approach for these no-option patients using adenoviral (Ad) intramyocardial vascular endothelial growth factor (VEGF)-B186 gene transfer, which induces myocardium-specific angiogenesis and arteriogenesis in pigs and rabbits. After acute infarction, AdVEGF-B186 increased blood vessel area, perfusion, ejection fraction, and collateral artery formation and induced changes toward an ischemia-resistant myocardial phenotype. Soluble VEGF receptor-1 and soluble neuropilin receptor-1 reduced the effects of AdVEGF-B186, whereas neither soluble VEGF receptor-2 nor inhibition of nitric oxide production had this result. The effects of AdVEGF-B186 involved activation of neuropilin receptor-1, which is highly expressed in the myocardium, via recruitment of G-protein-alpha interacting protein, terminus C (GIPC) and upregulation of G-protein-alpha interacting protein. AdVEGF-B186 also induced an antiapoptotic gene expression profile in cardiomyocytes and had metabolic effects by inducing expression of fatty acid transport protein-4 and lipid and glycogen accumulation in the myocardium. CONCLUSIONS: VEGF-B186 displayed strikingly distinct effects compared with other VEGFs. These effects may be mediated at least in part via a G-protein signaling pathway. Tissue-specificity, high efficiency in ischemic myocardium, and induction of arteriogenesis and antiapoptotic and metabolic effects make AdVEGF-B186 a promising candidate for the treatment of myocardial ischemia.

Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium.

OBJECTIVE: The endogenous role of the VEGF family member vascular endothelial growth factor-B (VEGF-B) in pathological angiogenesis remains unclear. METHODS AND RESULTS: We studied the role of VEGF-B in various models of pathological angiogenesis using mice lacking VEGF-B (VEGF-B(-/-)) or overexpressing VEGF-B(167). After occlusion of the left coronary artery, VEGF-B deficiency impaired vessel growth in the ischemic myocardium whereas, in wild-type mice, VEGF-B(167) overexpression enhanced revascularization of the infarct and ischemic border zone. By contrast, VEGF-B deficiency did not affect vessel growth in the wounded skin, hypoxic lung, ischemic retina, or ischemic limb. Moreover, VEGF-B(167) overexpression failed to enhance vascular growth in the skin or ischemic limb. CONCLUSIONS: VEGF-B appears to have a relatively restricted angiogenic activity in the ischemic heart. These insights might offer novel therapeutic opportunities.