Angiotensin-converting enzyme inhibition improves defective angiogenesis in the ischemic limb of spontaneously hypertensive rats.
OBJECTIVE
Natural angiogenesis has been shown to be impaired in spontaneously hypertensive rats (SHR). The purpose of this study was to determine whether pathological angiogenesis in the setting of tissue ischemia is also impaired in SHR, and to what extent it is modified by angiotensin-converting enzyme (ACE) inhibition.


METHODS
Ischemia was induced in the hindlimb of SHR by excision of the femoral artery, after which the animals were randomly assigned to receive low-dose perindopril (sub-antihypertensive, 0.2 mg/kg/day), high-dose perindopril (antihypertensive, 2.0 mg/kg/day), or vehicle for 3 weeks. Wistar-Kyoto rats (WKY) with femoral artery excision served as a control group.


RESULTS
Tissue ACE activity in SHR was significantly increased compared to WKY (49.4+/-6.2 vs. 34.0+/-14.2 IU/mg, P<0.01). Administration of perindopril significantly reduced ACE activity in SHR (low dose: 12.4+/-2.3; high dose: 11.0+/-2.1 IU/mg, P<0.005). Angiogenesis of the ischemic limb muscles was significantly impaired at 4 weeks in SHR versus WKY as indicated by the lower capillary density in the former (364.5+/-43.0 vs. 463.8+/-63.0/mm(2), P<0.05) as well as the reduced hindlimb perfusion assessed by laser Doppler imaging (0.86+/-0.08 vs. 1.03+/-0.09, P<0.05). Administration of perindopril significantly augmented both the capillary density (low dose: 494.3+/-69.8; high dose: 543.9+/-76.9/mm(2), P<0.005) and the limb perfusion (low dose: 1.06+/-0.15; high dose: 1.05+/-0.12, P<0.05) of the ischemic limb in SHR.


CONCLUSIONS
These findings indicate that pathological angiogenesis in the setting of tissue ischemia is impaired in SHR compared with WKY, and that this impairment can be reversed by ACE inhibition. The angiogenic properties of an ACE inhibitor may benefit patients with essential hypertension presenting with lower limb vascular insufficiency.
Takeshita
S
S
Department of Medicine, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi-ku, 173-8605, Tokyo, Japan.
Tomiyama
H
H
Yokoyama
N
N
Kawamura
Y
Y
Furukawa
T
T
Ishigai
Y
Y
Shibano
T
T
Isshiki
T
T
Sato
T
T
D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002196:Capillaries / Q000473:pathology; D006614:Hindlimb / Q000098:blood supply; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D007511:Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D020913:Perindopril / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012039:Regional Blood Flow / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril