Role of Bradykinin, Nitric Oxide, and Angiotensin II Type 2 Receptor in Imidapril-Induced Angiogenesis

Abstract

The angiotensin II (Ang II)-Ang II type 1 receptor pathway is proangiogenic, whereas studies showed that some angiotensin-converting enzyme inhibitors also stimulate angiogenesis in the setting of tissue ischemia, leaving a controversy of Ang II-mediated angiogenesis. We investigated whether an angiotensin-converting enzyme inhibitor imidapril-induced angiogenesis might be mediated via the tissue bradykinin pathway. To rule out the conventional effects of Ang II on angiogenesis, we used Ang II type 1a receptor knockout (AT1aKO) mice. We examined the effects of the angiotensin-converting enzyme inhibitor imidapril on angiogenesis in a hindlimb ischemia model using AT1aKO mice. After induction of hindlimb ischemia, AT1aKO mice were treated with or without imidapril (1.0 or 0.1 mg/kg per day for 21 days). Angiogenesis was quantified by laser Doppler blood flowmetry and capillary density. Angiogenesis was reduced in AT1aKO mice compared with wild-type mice. Imidapril with either low or high doses enhanced angiogenesis in AT1aKO mice (P<0.01). Ang II type 2 receptor antagonist (PD123319; 30 mg/kg per day) and B1 receptor antagonist (DesArg9-[Leu8]-bradykinin; 50 nmol/kg per day) suppressed the imidapril-induced angiogenesis in AT1aKO mice to an extent even lower than that of nontreated AT1aKO mice. B2 receptor antagonist (Hoechst 140; 100 microg/kg/d) and NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester; 20 mg/kg per day) moderately attenuated the imidapril-mediated angiogenesis. RT-PCR revealed that vascular endothelial growth factor receptor 2 mRNA was reduced with PD123319, DesArg9-[Leu8]-bradykinin, or Hoechst 140, and vascular endothelial growth factor mRNA abundance was suppressed with PD123319 or DesArg9-[Leu8]-bradykinin. In conclusion, imidapril elicited angiogenesis in the setting of tissue ischemia in AT1aKO mice. This angiogenic effect might involve the Ang II-Ang II type 2 receptor pathway in addition to the bradykinin-B1 and bradykinin-B2 receptor/NO-dependent pathways.

Amelioration of the nephrotoxic effect of potassium dichromate by whey protein and/or nigella sativa oil in male albino rats

“…So that, rats were intoxicated with K 2 Cr 2 O 7 with subsequent increase in the serum creatinine, urea, uric acid, proteins and sodium levels and severe alteration in the histopathological examination in comparison with normal control group, through the elevation of reactive oxygen species (ROS) that induces tissues damage such as liver, pancreas, cerebellum and kidney (Kim et al, 2005;Fatima et al, 2005). ROS generated by this process can bring on injury to cellular proteins, lipids, and DNA leading to oxidative stress (Li et al, 2008;Mehany et al, 2013).…”

Angiogenesis and hypertension: an update

“…ACE inhibition causes bradykinin (BK) to accumulate that increases pro-angiogenic inducers such as nitric oxide (NO) and vascular endothelial growth factor (VEGF) mainly by the BK type 2 receptor and its interaction with the VEGF receptor 2. 50,88,92 Also angiotensin II can be pro-angiogenic through the angiotensin type 2 receptor, which increases BK levels. 103 Angiotensin type 2 receptor may be specifically activated when angiotensin II type 1 receptor blockers (ARBs) block binding to the angiotensin type 1 receptor.…”

“…50 Further studies in rat models suggest that ACE-I-induced neovascularization depends on both BK B1 and B2 receptors. 12,91,92 The ACE-I captopril represents an exception to the 'rule' that ACE-Is are generally pro-angiogenic: captopril, with its reactive sulfhydryl group, inihibits metalloproteinases 93 and increases the formation of the endogenous and potent angiogenic inhibitor angiostatin. 94 Captopril reduced microvascular growth in hypertensive and normotensive rats 95 and the capillary-fibre ratio in ischaemic hind limbs of rats.…”

Human Urinary kallidinogenase promotes good recovery in ischemic stroke patients with level 3 hypertension

“…So it can expand blood vessels in the ischemic area, improve cerebral blood supply of penumbra, and restore the neurological deficit as soon as possible. Furthermore, kinins could induce the expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2), which then transactivates endothelial NO synthase and promotes new blood vessels formation (Ke & Jing, 2016;Li et al, 2008).…”