1α,25-Dihydroxyvitamin D3 Promotes Angiogenesis After Cerebral Ischemia Injury in Rats by Upregulating the TGF-β/Smad2/3 Signaling Pathway

Abstract

Stroke is a disease with high morbidity, disability and mortality, which seriously endangers the life span and quality of life of people worldwide. Angiogenesis and neuroprotection are the key to the functional recovery of penumbra function after acute cerebral infarction. In this study, we used the middle cerebral artery occlusion (MCAO) model to investigate the effects of 1α,25-dihydroxyvitamin D3 (1,25-D3) on transforming growth factor-β (TGF-β)/Smad2/3 signaling pathway. Cerebral infarct volume was measured by TTC staining. A laser speckle flow imaging system was used to measure cerebral blood flow (CBF) around the ischemic cortex of the infarction, followed by platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31) and isolectin-B4 (IB4) immunofluorescence. The expression of vitamin D receptor (VDR), TGF-β, Smad2/3, p-Smad2, p-Smad3, and vascular endothelial growth factor (VEGF) was analyzed by western blot and RT-qPCR. Results showed that compared with the sham group, the cerebral infarction volume was significantly increased while the CBF was reduced remarkably in the MCAO group. 1,25-D3 reduced cerebral infarction volume, increased the recovery of CBF and expressions of VDR, TGF-β, p-Smad2, p-Smad3, and VEGF, significantly increased IB4+ tip cells and CD31+ vascular length in the peri-infarct area compared with the DMSO group. The VDR antagonist pyridoxal-5-phosphate (P5P) partially reversed the neuroprotective effects of 1,25-D3 described above. In summary, 1,25-D3 plays a neuroprotective role in stroke by activating VDR and promoting the activation of TGF-β, which in turn up-regulates the TGF-β/Smad2/3 signaling pathway, increases the release of VEGF and thus promotes angiogenesis, suggesting that this signaling pathway may be an effective target for ischemic stroke treatment. 1,25-D3 is considered to be a neuroprotective agent and is expected to be an effective drug for the treatment of ischemic stroke and related diseases.

Transcriptome‐wide profile of 1α,25 dihydroxyvitamin D3 in HTR‐8/SVneo cells

“…Relevant work has yielded similar results. 23,32,33 This study revealed specific differential genes account for a high proportion at different concentrations. For low concentrations of 1,25(OH) 2 D 3 , UCP3, a member of the mitochondrial uncoupling protein family, was specifically expressed.…”

“…Similar results were described in the study of enterocyte‐like Caco‐2 cells, in which 1,25 (OH) 2 D 3 stimulates mitogen activated protein kinase and extracellular regulated protein kinases 5 to activate transcription factor Ets‐1 by phosphorylation, and Ets‐1 can enhance CYP24A1 promoter transcriptional activity and promote CYP24A1 transcriptional expression 31 . Through KEGG analysis, we could find that 1,25(OH) 2 D 3 mainly plays a role through “cytokine‐cytokine receptor interaction,” “TGF‐beta signaling pathway” and “hippo signaling pathway.” Relevant work has yielded similar results 23,32,33 …”

Calcipotriol Attenuates Form Deprivation Myopia Through a Signaling Pathway Parallel to TGF-β2–Induced Increases in Collagen Expression

“… 25 , 42 Such declines may contribute to long-term collagen fibril diameter thinning observed in highly myopic eyes. 43 , 44 A complex interplay between the TGF-β and VDR signaling pathways has been described in recent studies in different tissues, 28 – 30 , 45 , 46 and they define a role for VDR as an endocrine checkpoint to modulate liver fibrosis. 28 On the other hand, vitamin D3 increased the expression of TGF-β and TGFBRI/II in osteoblasts 47 and patients with multiple sclerosis.…”

A cuproptosis-related signature for predicting the prognosis of gastric cancer

“…The TGF-β signaling pathway is well known for its role in carcinogenesis and progression, promoting tumor migration and invasion. 1α,25-dihydroxyvitamin D3 upregulates the TGF-β/Smad2/3 signaling pathway, which promotes angiogenesis in rats (38). Cytochrome P450 induces mutations and cell transformation by covalent binding of DNA with electrophilic intermediates produced by the activation of numerous carcinogenic chemicals, ultimately leading to cancer development (39).…”