Related Experiment Video
Updated: Aug 21, 2026
Improved Renal Denervation Mitigated Hypertension Induced by Angiotensin II Infusion
Published on: May 26, 2022
Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice
Téni G Ebrahimian1, Radia Tamarat, Michel Clergue
1INSERM U541, Hôpital Lariboisière, IFR Circulation-Lariboisière, Université Paris, France.
Objective:
We analyzed the beneficial therapeutic effect of angiotensin converting enzyme inhibitor (ACEI) on both retinal and hind limb neovascularization in diabetic mice.
Methods And Results:
Diabetic mice (streptozotocin, 40 mg/kg) were treated with or without ACEI (Perindopril, 3 mg/kg per day) or AT1 receptor blocker (Candesartan, 20 mg/kg) for 4 months. Hind limb ischemia was then induced by right femoral artery ligature for 1 additional month. In the ischemic leg, angiographic score, capillary density, and foot perfusion were increased by 2.7, 2.0-fold, and 1.6-fold, respectively, in ACEI-treated diabetic mice compared with untreated diabetic animals (P<0.01). ACEI also raised vascular endothelial growth factor (VEGF) protein level by 1.4-fold in ischemic diabetic leg. This ACEI pro-angiogenic effect was totally blunted in diabetic bradykinin B2 receptor-deficient animals, suggesting that it was mediated by the bradykinin pathway. In the diabetic retina, angiotensinogen and ACE mRNA levels were increased by 2.8-fold and 4.1-fold, respectively (P<0.01 versus nondiabetic mice), highlighting a local activation of renin-angiotensin system. Diabetes also raised VEGF protein level by 1.5-fold (P<0.05 versus nondiabetic mice). Treatments with ACEI and AT1 receptor blocker hampered diabetes-induced VEGF upregulation and retinal neovascularization.
Conclusions:
ACE inhibition improved neovascularization in the diabetic ischemic leg through activation of bradykinin signaling, whereas it reduced vessel growth in the diabetic retina through inhibition of overacting Ang II pathway.
Insights
Angiotensin converting enzyme inhibitor (ACEI) therapy promotes beneficial blood vessel growth in diabetic ischemic limbs via bradykinin signaling. However, ACEI reduces pathological vessel growth in the diabetic retina by inhibiting the Ang II pathway.
Area of Science:
- Cardiovascular Research
- Diabetic Complications
- Angiogenesis Research
Background:
- Diabetes mellitus is associated with microvascular complications, including neovascularization in the retina and impaired blood flow in the limbs.
- The renin-angiotensin system (RAS) plays a critical role in regulating vascular function and is often dysregulated in diabetes.
- Angiotensin converting enzyme inhibitors (ACEI) are widely used to manage cardiovascular diseases, but their specific effects on diabetic neovascularization require further elucidation.
Purpose of the Study:
- To investigate the therapeutic effects of ACE inhibition on retinal and hind limb neovascularization in a mouse model of diabetes.
- To explore the underlying molecular mechanisms, including the roles of bradykinin and the Ang II pathway.
Main Methods:
- Diabetic mice were treated with ACEI (Perindopril) or an AT1 receptor blocker (Candesartan).
- Hind limb ischemia was surgically induced, and neovascularization was assessed via angiography, capillary density, and perfusion.
- Retinal neovascularization was evaluated, and gene/protein expression of angiotensinogen, ACE, and VEGF was measured.
Main Results:
- ACEI treatment significantly improved neovascularization in the ischemic hind limb of diabetic mice, indicated by increased angiographic score, capillary density, and foot perfusion.
- ACEI increased vascular endothelial growth factor (VEGF) levels in ischemic limbs, an effect dependent on the bradykinin B2 receptor.
- In the diabetic retina, ACEI and AT1 receptor blocker reduced diabetes-induced VEGF upregulation and neovascularization, suggesting inhibition of the Ang II pathway.
Conclusions:
- ACE inhibition promotes beneficial angiogenesis in diabetic ischemic limbs through bradykinin pathway activation.
- Conversely, ACE inhibition mitigates pathological neovascularization in the diabetic retina by suppressing the overactive Ang II pathway.
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:10Mechanism of Angiogenesis
01:26Heart Failure Drugs: Inhibitors of Renin-Angiotensin System