动物造模,病理性视网膜新生血管 z-bo 2022-02-06 366

　　Introduction: Pathological retinal neovascularization is the main cause of retinopathy of prematurity, macular telangiectasia of prematurity, diabetic retinopathy and age-related macular degeneration. The current methods of treating retinal neovascularization have limitations. Although laser photocoagulation helps maintain central vision, it can cause peripheral vision loss. In addition, anti-vascular endothelial growth factor (anti-vascular endothelial growth factor) drugs can effectively treat some patients, but not all patients have an impact on neovascularization, including degeneration of normal blood vessels, neural retina and choroid. Therefore, better therapeutic agents are needed to effectively treat vision-threatening neovascularization. Fibroblast growth factors (FGFs) are generally believed to promote the angiogenic response. FGF21, a member of the FGF family, is considered to be a pro-angiogenic factor in the body in experiments of subcutaneous silicon tube implantation in mice. FGF21 inhibits pathological angiogenesis in the retina and choroid of the eye in three different mouse disease models. In humans, the administration of long-acting FGF21 analogs increases circulating adiponectin (APN) in a dose-dependent manner. In mice, FGF21 administration increases APN production to regulate glucose and lipid metabolism. Low circulating APN levels may contribute to the development of human neovascular eye disease. The inhibitory effect of APN on choroidal neovascularization in rodent retina. To explore the role of FGF21 in (1) hypoxia-induced neovascular retinopathy. (2) Retinal neovascularization driven by lack of energy, (3) Laser induced choroidal neovascularization.

　　Results and discussion: FGF21 inhibits hypoxia-induced retinal neovascularization: early retinopathy of prematurity and diabetic retinopathy, early blood vessel growth stops or blood vessel loss leads to hypoxia and nutritional deficiency, which leads to excessive blood vessel growth. To investigate the effect of FGF21 on the growth of hypoxic pathological neovascularization, we used FGF21 to study oxygen-induced retinopathy in mice. After being exposed to 75% oxygen for 5 days, the pups that were nursing mother mice returned to the indoor air. Oxygen exposure causes occlusion of central retinal vessels. Hypoxia and hypoxia induce neovascularization in the retina. Extends from the retina to the vitreous at the boundary between the blood vessel and the non-vascularized area. Mouse pups were injected intraperitoneally with natural FGF21, long-acting FGF21 analogs, or excipients for 5 days. Natural FGF21 with a short half-life (0.4 hours) does not affect neovascularization, while PF-0523 1023 with a biological half-life of 28 hours significantly reduces neovascularization. To confirm the role of FGF21 in retinal neovascularization, we compared wild-type (FGF21+/+) and knock-out (FGF21-/-) mice to study the effect of FGF21 deficiency on oxygen-induced retinopathy. The number of new blood vessels in FGF21-/- mice increased. Compared with the strong inhibition of PF-0523 1023 on pathological neovascularization, the lack of natural FGF21 and endogenous FGF21 has a smaller effect on retinal neovascularization, which may be due to the short half-life and low internalization of natural FGF21 (0.4 hours). Source FGF21 levels. To determine whether FGF21 directly inhibited neovascularization, intravitreal injection of PF-0523 1023 reduced retinal neovascularization compared with injection of the contralateral eye. FGF21 can also promote retinal revascularization through APN, although APN is not required as a basic revascularization procedure in oxygen-induced retinopathy (OIR). Improved revascularization will tend to reduce the stimulation of proliferative neovascularization. FGF21 acts by interacting with its receptor FGFR1 and co-receptor β-kLotho (KLB). We found that FGF21 receptor 1, 2, 3, 4 and KLB mRNA are all expressed in the mouse retina. FGFR1 and FGFR3 are highly expressed in neovascularization and co-localize with APN. PF 0523 1023 is administered on the 17th day after birth (P17) to increase retinal APN, which is an important mediator of FGF21's metabolic function. The APN receptor agonist AdiPuron inhibits endothelial cell function in vitro. To determine whether APN mediates the protective effect of FGF21 on retinal neovascularization, we studied the role of the retinal vasculature (PN-0523 1023) of APN knockout (APN -/-) mice in oxygen-induced retinopathy. We found that APN deficiency aggravated the lack of retinal neovascularization and APN, and completely eliminated the beneficial effect of PF 0523 1023 on hypoxic retinal neovascularization. APN inhibits retinal neovascularization by reducing tumor necrosis factor alpha (TNF-α). It was found that PF-0523 1023 inhibited the expression of TNFα in the neovascular wild-type (WT) retina, but the lack of APN inhibited the expression of TNFα. FGF21 inhibits the growth of retinal neovascularization, possibly by targeting APN and reducing TNF-α, which is a key risk factor for oxygen-induced retinopathy. Every year, more than 15 million babies are born with congenital vascularization of the retina at birth. If normal vascularization does not occur after birth, it is the stage of development of proliferative retinopathy. Retinopathy of prematurity is the main cause of blindness in children. We have shown that low serum APN levels in preterm infants are positively correlated with proliferative retinopathy. Increasing circulating APN levels is related to the decrease of retinal neovascularization in mice. In oxygen-induced retinopathy in mice, administration of FGF21 increases retinal APN levels, reduces TNF-α levels, and inhibits pathological neovascularization. Diabetic retinopathy currently afflicts 93 million people worldwide, of which 28 million have visually threatening proliferative retinopathy. The level of FGF21 in patients with type 1 diabetes was lower than that in healthy controls. In streptozotocin-induced type 1 diabetic mice, FGF21 analogs reduced glucose uptake in brown adipose tissue and lowered blood sugar levels. FGF21 prevents kidney lipid accumulation and renal function decline in type 1 diabetic mice. Among patients with type 2 diabetes, serum FGF21 levels in patients with retinopathy are higher than those without retinopathy. FGF21 treatment reduces body weight and improves the lipid profile of type 2 diabetic patients, non-human primates and obese rodents, suggesting that FGF21 may play a beneficial role in diabetes and diabetic complications such as diabetic retinopathy. The mouse model of oxygen-induced retinopathy is often used for hypoxia-induced neovascularization in proliferative diabetic retinopathy. Therefore, our results also indicate that FGF21 may help prevent proliferative diabetic retinopathy. In the animal models of type 1 diabetes and type 2 diabetes, it is necessary to further study the role of FGF21 in early diabetic retinal vascular damage and late neovascularization of diabetic retinopathy.

　　The protective effect of FGF21 on retinal neovascularization caused by energy deficiency in VLDLR-/- mice: In addition to lack of oxygen, insufficient energy supply can also drive retinal neovascularization. The loss of low-density lipoprotein receptor (VLDLR) is related to the proliferation of retinal hemangioma and choroidal neovascularization, similar to the neovascularization of macular telangiectasia and advanced proliferative macular degeneration. In Vldlr-/- mice, abnormal blood vessels extend to photoreceptor cells. In order to evaluate whether FGF21 can prevent metabolically induced pathological neovascularization, we injected PF-0523 1023 into VLDLR-/- mice intraperitoneally from P8 to P15 every day at 0.5 mg/kg each time. PF-0523 1023 administration alleviates the neovascularization of VLDLR-/- mice, increases retinal APN, and reduces TNFα.

　　FGF21 inhibits laser-induced choroidal neovascularization in mice: choroidal neovascularization is a visual threat in age-related macular degeneration, in which the neovascularization expands from choroidal capillaries to the subretinal space. In a mouse model of laser-induced choroidal neovascularization, Bruch's membrane was destroyed by laser burns to induce choroidal neovascularization. In 6-8 weeks old C57B/6J mice, 10 mg/kg was administered every other day for 1 week before laser injury PF 0523 1023. In the mouse choroidal neovascularization model, PF-0523 1023 also induced a decrease in APN and TNFα in the choroidal-retinal complex. Neovascularization is the main cause of vision loss in patients with age-related macular degeneration and macular telangiectasia. Metabolic changes in retinal pigment epithelial cells and photoreceptors contribute to disease progression. In Vldlr-/- mice, insufficient fuel supply leads to retinal neovascularization, and FGF21 administration reduces the formation of neovascular disease. Our findings indicate that FGF21 administration may impair the development of metabolically driven retinal neovascularization, some aspects of macular telangiectasia and neovascular age-related macular degeneration. In the inflammatory aspect of laser-induced choroidal neovascularization modeling, neovascular age-related macular degeneration, FGF21 also inhibits pathological choroidal angiogenesis in adult mice. We determined that FGF21 can inhibit APN-mediated retinal and choroidal neovascularization. The effect of APN on the transcription and mRNA stability of TNF-α in macrophages... Inhibition of TNF-α leads to a decrease in retinal and choroidal neovascularization, which may be caused by increasing the germination of endothelial cells. FGF21 promotes the migration of human retinal microvascular endothelial cells. Different target systems may be affected by the opposite effect of FGF21 and angiogenesis. The research results also show that the inhibitory effect of FGF21 on retinal and choroidal neovascularization has nothing to do with VEGFA.