TGFβ-Neurotrophin Interactions in Heart, Retina, and Brain

Abstract

Ischemic insults to the heart and brain, i.e., myocardial and cerebral infarction, respectively, are amongst the leading causes of death worldwide. While there are therapeutic options to allow reperfusion of ischemic myocardial and brain tissue by reopening obstructed vessels, mitigating primary tissue damage, post-infarction inflammation and tissue remodeling can lead to secondary tissue damage. Similarly, ischemia in retinal tissue is the driving force in the progression of neovascular eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD), which eventually lead to functional blindness, if left untreated. Intriguingly, the easily observable retinal blood vessels can be used as a window to the heart and brain to allow judgement of microvascular damages in diseases such as diabetes or hypertension. The complex neuronal and endocrine interactions between heart, retina and brain have also been appreciated in myocardial infarction, ischemic stroke, and retinal diseases. To describe the intimate relationship between the individual tissues, we use the terms heart-brain and brain-retina axis in this review and focus on the role of transforming growth factor β (TGFβ) and neurotrophins in regulation of these axes under physiologic and pathologic conditions. Moreover, we particularly discuss their roles in inflammation and repair following ischemic/neovascular insults. As there is evidence that TGFβ signaling has the potential to regulate expression of neurotrophins, it is tempting to speculate, and is discussed here, that cross-talk between TGFβ and neurotrophin signaling protects cells from harmful and/or damaging events in the heart, retina, and brain.

Deficiency in Retinal TGFβ Signaling Aggravates Neurodegeneration by Modulating Pro-Apoptotic and MAP Kinase Pathways

“…We have recently demonstrated that expression of the neurotrophin Ngf is dependent upon TGFβ2 treatment in vitro and is significantly enhanced in the juvenile retina of a mouse model with increased TGFβ signaling activity [ 12 ]. Hence, the fact that ‘p75 neurotrophin receptor’ was amongst the genes that were upregulated in VPP but not regulated in double mutant retinae might point towards an interaction of neurotrophin and TGFβ signaling, as postulated in previously published manuscripts from our group [ 12 , 34 ] and others [ 43 , 44 , 45 ].…”

“…TGFβ signaling has a plethora of different functions such as cell-cycle control, cell differentiation, and regulation of early development [ 31 , 32 , 33 , 34 ]. As the Cre recombinase in Tgfbr2 ΔOC retinae is constitutively expressed from embryonic day 10.5 in all cells deriving from the inner layer of the optic cup e.g., retinal neurons and Müller cells [ 35 ], we addressed potential developmental-related aspects in the Tgfbr2 ΔOC model in one of our previously published manuscripts [ 12 ].…”

“…Moreover, gene ontology analyses suggested an upregulation of ‘cell cycle negative regulation of p75 neurotrophin receptor’ in VPP, but not in double mutant retinae. P75 neurotrophin receptor is one of the neurotrophin receptors, mediating predominately pro-apoptotic effects [ 34 , 42 ]. We have recently demonstrated that expression of the neurotrophin Ngf is dependent upon TGFβ2 treatment in vitro and is significantly enhanced in the juvenile retina of a mouse model with increased TGFβ signaling activity [ 12 ].…”

The Protective Effects of Neurotrophins and MicroRNA in Diabetic Retinopathy, Nephropathy and Heart Failure via Regulating Endothelial Function

“…Studies of the molecular interactions of BDNF and NGF in the diabetic retina have shown that both molecules exhibit pro-angiogenic effects and contribute to the formation of neovascularization in proliferative diabetic retinopathy [ 176 ]. This is either directly, by binding to Trk receptors on endothelial cells, or indirectly, by promoting vascular endothelial growth factor (VEGF) expression in other cells [ 177 , 181 , 182 , 183 , 184 , 185 , 186 ]. Thus, inhibition of VEGF by intravitreal injection of bevacizumab, a humanized anti-VEGF monoclonal antibody commonly used to inhibit neovascularization in patients with proliferative diabetic retinopathy, results in marked reduction of retinal NGF levels [ 187 ].…”

Study of the Level of Pro- and Antiangiogenic Growth Factors in Vitreous Fluid in Neovascular Age-Related Macular Degeneration on the Background of Treatment

“…К естественным ингибиторам ангиогенеза относят следующие цитокины: фактор пигментного эпителия (PEDF), ангиостатин, эндостатин, TGF-β, IFN-γ, IFN-α и все тот же TNF-α, который при длительном воздействии на ЭК тормозит их пролиферацию и в итоге запускает их апоптоз [11,15,17]. Трансформирующий фактор β (TGF-β) -многофункциональная молекула, секретируемая многими клетками глаза: РПЭ, клетками Мюллера, ЭК, перицитами, фоторецепторами, астроцитами и выполняющая в глазу различные функции, касающиеся регуляции роста, пролиферации, миграции, апоптоза, нейропротекции, иммунной привилегированности глаза и многого другого [18]. Что касается неоангиогенеза, то TGF-β может выполнять как про-, так и антиангиогенную роль.…”