Inhibition of HIF-1α Reduced Blood Brain Barrier Damage by Regulating MMP-2 and VEGF During Acute Cerebral Ischemia

Abstract

Increase of blood brain barrier (BBB) permeability after acute ischemia stroke is a predictor to intracerebral hemorrhage transformation (HT) for tissue plasminogen activator (tPA) thrombolysis and post-endovascular treatment. Previous studies showed that 2-h ischemia induced damage of BBB integrity and matrix metalloproteinase-2 (MMP-2) made major contribution to this disruption. A recent study showed that blocking β2-adrenergic receptor (β2-AR) alleviated ischemia-induced BBB injury by reducing hypoxia-inducible factor-1 alpha (HIF-1α) level. In this study, we sought to investigate the interaction of HIF-1α with MMP-2 and vascular endothelial growth factor (VEGF) in BBB injury after acute ischemia stroke. Rat suture middle cerebral artery occlusion (MCAO) model was used to mimic ischemia condition. Our results showed that ischemia produced BBB damage and MMP-2/9 upregulation was colocalized with Rhodamine-dextran leakage. Pretreatment with YC-1, a HIF-1α inhibitor, alleviated 2-h ischemia-induced BBB injury significantly accompanied by decrease of MMP-2 upregulation. In addition, YC-1 also prevented VEGF-induced BBB damage. Of note, VEGF was shown to be colocalized with neurons but not astrocytes. Taken together, BBB damage was reduced by inhibition of interaction of HIF-1α with MMP-2 and VEGF during acute cerebral ischemia. These findings provide mechanisms underlying BBB damage after acute ischemia stroke and may help reduce thrombolysis- and post-endovascular treatment-related cerebral hemorrhage.

Effect of X-rays on transcript expression of rat brain microvascular endothelial cells: role of calcium signaling in X-ray-induced endothelium damage

“…Therefore, based on these evidences, we hypothesize that increased expression of NGF in the radiation treatment maybe has a protective effect on the BMECs. Moreover, one study reported that inhibition of Hif1a-encoded protein attenuated BBB damage in acute cerebral ischemia, and we also found that Hif1a mRNA was down-regulated by radiation treatment in the present study [42], while deficiency of Cdc42-encoded protein also displayed increased vascular permeability in vivo and activation of CDC42 might protect endothelial barrier [43,45]. Moreover, it is interesting that one study showed that Rhog-encoded protein played an essential role of angiogenesis in vascular endothelial cells via mediating the CDC42 [46].…”

“…The Vegfa-encoded protein induces proliferation and migration of vascular endothelial cells and is essential for both physiological and pathological angiogenesis. It also has anti-angiogenic and vascular permeability-inducing functions [41,42]. We believe that up-regulated VEGFA protein may lead to increased microvascular permeability in the brain.…”

miR-183-5p alleviates early injury after intracerebral hemorrhage by inhibiting heme oxygenase-1 expression

“…Lpxn [ 48 ], Sucnr1 [ 49 ], and Csf2rb2 [ 50 ] seem to be related to the migration of macrophages. Ptbp3 [ 51 ] can promote the growth and metastasis of colorectal cancer through the activation of HIF-1α, and HIF-1α is involved in the ICH process [ 52 ]. After ICH, these mRNAs may compete with HO-1 mRNA to combine miR-183-5p and may affect the regulation of ICH processes by miR-183-5p.…”

Dl-NBP (Dl-3-N-Butylphthalide) Treatment Promotes Neurological Functional Recovery Accompanied by the Upregulation of White Matter Integrity and HIF-1α/VEGF/Notch/Dll4 Expression

“…Using stroke-prone renovascular hypertensive rats (RHRSP) to mimic hypertension, Liao et al, reported that dl-NBP treatment after a photochemical reaction-induced focal permanent MCAO model increased the quantity of CD31positive vessels and upregulated expressions of HIF-1a and VEGF (Liao et al, 2009), which play important roles in angiogenesis, vasculogenesis (Leung et al, 1989), and strokeinduced BBB damage (Sun et al, 2017a;Shen et al, 2018). Our result showed that dl-NBP treatment increased the number of RECA-1 positive vessels after focal transient ischemic stroke, accompanied by upregulated HIF-1a and VEGF, suggesting that dl-NBP treatment may increase the number of RECA-1-positive vessels though upregulating HIF-1a and VEGF after focal transient ischemic stroke in non-hypertension patients.…”

“…Immunostaining for RECA-1, HIF-1a, VEGF, Dll-4, Notch, CC1, and MBP As we described previously, the 20-mm-thick brain slice was fixed with 4% paraformaldehyde (PFA) for further analysis (Shen et al, 2018). In brief, blocking buffer (0.3% Triton X-100 and 10% normal goat serum) was applied for 2 h to block nonspecific binding and primary antibody of HIF-1a (1:100; Novus), VEGF (1:100; Abcam), Dll4 (1:50; Abcam), RECA-1 (1:50; Abcam), Notch (1:50; Cell Signaling Technology), CC1 (1:100; Abcam), and MBP (1:200; Cell Signaling Technology) were incubated overnight at 4°C.…”