Eph-B4 prevents venous adaptive remodeling in the adult arterial environment

Stimulation of Eph-B4 prevents adaptive remodeling and preserves venous identity when veins are surgically placed into an arterial environment

Limb ischemia after iliac ligation in aged mice stimulates angiogenesis without arteriogenesis

Older patients are thought to tolerate acute ischemia more poorly than younger patients. Since aging may depress both angiogenesis and arteriogenesis, we determined the effects of age on both angiogenesis and arteriogenesis in a model of severe acute limb ischemia. Young adult (3-months-old) and aged (18-months-old) C57BL/6 mice underwent right common iliac artery and vein ligation and transection. Data were collected on days 0, 7, and 14. Perfusion was measured with a laser Doppler scan and compared to the contralateral limb. Functional deficits were evaluated with the Tarlov scale. Capillary density and endothelial progenitor cell (EPC) number were determined by direct counting lectin-positive/alpha-actin-negative cells and VEGFR2/CXCR4 dually-positive cells, respectively; angiography was performed to directly assess arteriogenesis. Young adult and aged mice had a similar degree of decreased perfusion after iliac ligation (young, n = 15: 20.4 ± 1.9%, vs aged, n = 20: 19.6 ± 1.3%; P = .72, analysis of variance [ANOVA]); however, young mice recovered faster and to a greater degree than aged mice (day 7, 35 ± 6% vs 17 ± 4%, P = .046; day 14, 60 ± 5% vs 27 ± 7%, P = .0014). Aged mice had worse functional recovery by day 14 compared to young mice (2.3 ± 0.3 vs 4.3 ± 0.4; P = .0021). Aged mice had increased capillary density (day 7, 12.9 ± 4.4 vs 2.8 ± 0.3 capillaries/hpf; P = .02) and increased number of EPC incorporated into the ischemic muscle (day 7, 8.1 ± 0.9 vs 2.5 ± 1.9 cells; P = .007) compared to young mice, but diminished numbers of collateral vessels to the ischemic limb (1 vs 9; P = .01), as seen on angiography. After severe hind limb ischemia, aged animals become ischemic to a similar degree as young animals, but aged animals have significantly impaired arteriogenesis and functional recovery compared to younger animals. These results suggest that strategies to stimulate arteriogenesis may complement those that increase angiogenesis, and may result in improved relief of ischemia. The incidence of chronic limb ischemia increases with age as do the consequences of acute ischemia. We show, using a new model of severe acute limb ischemia that does not wound the ischemic limb, that aged mice increase angiogenesis in response to acute ischemia, but do not show arteriogenesis, ie, large collateral formation. These results suggest why elderly patients develop large vessel disease such as claudication but can still heal small wounds. They also suggest that strategies to treat ischemia in elderly patients should focus on stimulating large vessel arteriogenesis, rather than solely small vessel angiogenesis