title: Aging-induced collateral dysfunction: impaired responsiveness of collaterals and susceptibility to apoptosis via dysfunctional eNOS signaling.
abstract: Despite positive animal studies, clinical angiogenesis trials have been disappointing, possibly due to risk factors present in humans but usually unexplored in animals. We recently demonstrated aging causes impaired collateral remodeling and collateral dropout; here, we investigate potential mechanisms responsible for these findings. Four-, 10-, and 18-month-C57BL/6J mice were subjected to femoral artery ligation; flow was measured using laser Doppler perfusion imaging. Endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS were measured in calf muscle. Apoptosis was assessed in endothelial (EC) and smooth muscle (SMC) cells isolated from young and old mice. Angiogenesis was measured using a Matrigel plug assay. Lethally irradiated young and old mice received bone marrow cells (BMC) from either young or old donors and were subjected to femoral artery ligation (FAL). BMC mobilization and homing were assessed. Flow recovery was impaired and less eNOS and phosphorylated eNOS was present in older vs. young mice (p < 0.001 and p = 0.015, respectively). ECs and SMCs from older mice were more sensitive to an apoptotic stimulus, but were rescued by NO-enhancing drugs. In older mice, angiogenesis (Matrigel plug assay) was impaired, as was mobilization and homing of BM progenitor cells following FAL. Although both mobilization and homing improved when older mice received BMC transplantation from young donors, flow recovery failed to improve. Aging impairs BMC mobilization and homing, collateral responsiveness to angiogenic stimuli, and increases EC and SMC susceptibility to apoptosis via dysfunctional eNOS signaling. The latter could contribute to impaired remodeling and collateral dropout. These finding identify potential obstacles to therapeutic interventions in elderly patients.
authors.affiliation: Cardiovascular Research Institute, MedStar Health Research Institute, Washington, DC 20010, USA.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Wang
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Peng
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Lassance-Soares
authors.forename: Amir H
authors.initials: AH
authors.lastname: Najafi
authors.forename: Lee O
authors.initials: LO
authors.lastname: Alderman
authors.forename: Subeena
authors.initials: S
authors.lastname: Sood
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: Xue
authors.forename: Rosanna
authors.initials: R
authors.lastname: Chan
authors.forename: James E
authors.initials: JE
authors.lastname: Faber
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Epstein
authors.forename: Mary Susan
authors.initials: MS
authors.lastname: Burnett
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001011:Aorta / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D017209:Apoptosis; D001157:Arterial Occlusive Diseases / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D003097:Collateral Circulation; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology; D005260:Female; D005263:Femoral Artery / Q000601:surgery; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D035002:Lower Extremity / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000201:enzymology; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D055420:Perfusion Imaging / Q000379:methods; D010766:Phosphorylation; D012039:Regional Blood Flow; D015398:Signal Transduction
chemical_list: D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517382:Pde5a protein, mouse