Vascular Protection by Angiotensin Receptor Antagonism Involves Differential VEGF Expression in Both Hemispheres after Experimental Stroke

Abstract

We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset Vascular restoration by candesartan after stroke maybe related to differential regional upregulation of VEGFB and VEGFA, promoting a “prosurvival state” in the ischemic hemisphere and angiogenesis in the contralesional side, respectively. These vascular changes in both hemispheres after effective treatment are likely to contribute to enhanced recovery after stroke.

Candesartan Induces a Prolonged Proangiogenic Effect and Augments Endothelium-Mediated Neuroprotection after Oxygen and Glucose Deprivation: Role of Vascular Endothelial Growth Factors A and B

“…Our findings show an increased expression of both isoforms in the ipsilateral and the contralateral hemispheres. Nevertheless, VEGF-A upregulation was more pronounced and lasted longer in the contralateral hemisphere, suggesting a role of this hemisphere in the process of recovery (Guan et al, 2011c). The increase in VEGF-B, on the other hand, was most pronounced at 8 hours in the ipsilateral hemisphere, consistent with its main role as a prosurvival factor.…”

“…This effect was evident by the ability of the CSF, collected at different time points, to transform brain endothelial cells into tube-like structures resembling blood vessels in vitro. Our previous work linked candesartan's beneficial effects to enhanced production of VEGF-A, the prototypical angiogenic molecule, as well as the relatively new VEGF isoform, VEGF-B (Guan et al, 2011c). The exact function of VEGF-B is still controversial.…”

“…Protein expression was measured by Western blotting as previously described (Guan et al, 2011c). Nonspecific binding was blocked by incubating the membranes in 5% milk in Trisbuffered saline/Tween 20 for 60 minutes prior to overnight incubation with primary antibodies against VEGF-A, phospho-VEGFR-1 (Tyr 1213; Millipore, Billerica, MA), VEGF-B (Abcam, Cambridge, MA), HIF-1a, Ang-1 (Santa Cruz Biotechnology, Dallas, TX), total VEGFR-1, phospho-VEGFR-2 (Tyr996), total VEGFR-2, glyceraldehyde-3-phosphate dehydrogenase, and cleaved caspase-3 (Cell Signaling Technology, Danvers, MA).…”

Cerebral Neovascularization in Diabetes: Implications for Stroke Recovery and beyond

“…90 Recently, we showed that the angiotensin II type 1 receptor antagonist, candesartan, when administered at reperfusion in a rat model of temporary MCAO, promoted recovery and angiogenesis in the contralesional striatum at 7 days after the stroke. 99 This was confirmed in a more recent investigation where normoglycemic rats showed increased angiogenesis and recovery after stroke compared with diabetic animals, where vascular regression after stroke accompanied a much poorer functional outcome. 100 In summary, angiogenesis occurs after stroke and is closely linked to recovery.…”

AT1 Receptor Antagonism Is Proangiogenic in the Brain: BDNF a Novel Mediator

“…Of interest, the angiogenic response of candesartan was maintained even in nonstroked rats (Kozak et al, 2009). Subsequently, it was demonstrated that candesartan increased the expression of a number of genes for proangiogenic growth factors, including brain-derived neurotrophic factor (BDNF), after experimental cerebral ischemia (Guan et al, 2011). BDNF is a member of the neurotrophin family that is expressed in a number of cell types and has been shown to have potent neurogenic, neuroprotective, and angiogenic effects (Caporali and Emanueli, 2009;Greenberg et al, 2009).…”