title: p-Hydroxybenzyl alcohol-containing biodegradable nanoparticle improves functional blood flow through angiogenesis in a mouse model of hindlimb ischemia.
abstract: Therapeutic angiogenesis has achieved promising results for ischemic diseases or peripheral artery disease in preclinical and early-phase clinical studies. We examined the therapeutic angiogenic effects of HPOX, which is biodegradable polymer composing the antioxidant p-hydroxybenzyl alcohol (HBA), in a mouse model of hindlimb ischemia. HPOX effectively stimulated blood flow recovery, compared with its degraded compounds HBA and 1,4-cyclohexendimethanol, via promotion of capillary vessel density in the ischemic hindlimb. These effects were highly correlated with levels of angiogenic inducers, vascular endothelial cell growth factor (VEGF), heme oxygenase-1 (HO-1), and Akt/AMPK/endothelial nitric oxide synthase (eNOS) in ischemic mouse hindlimb muscle. Blood perfusion and neovascularization induced by HPOX were reduced in eNOS(-/-) and HO-1(+/-) mice. HPOX also elevated the endothelial cell markers VEGF receptor-2, CD31, and eNOS mRNAs in the ischemic hindlimb, indicating that HPOX increases endothelial cell population and angiogenesis in the ischemic muscle. However, this nanoparticle suppressed expression levels of several inflammatory genes in ischemic tissues. These results suggest that HPOX significantly promotes angiogenesis and blood flow perfusion in the ischemic mouse hindlimb via increased angiogenic inducers, along with suppression of inflammatory gene expression. Thus, HPOX can be used potentially as a noninvasive drug intervention to facilitate therapeutic angiogenesis.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, College of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
authors.forename: Byung-Ryul
authors.initials: BR
authors.lastname: Cho
authors.affiliation: Division of Cardiology, Department of Internal Medicine, College of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
authors.forename: Dong Ryeol
authors.initials: DR
authors.lastname: Ryu
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
authors.forename: Kwang-Soon
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
authors.forename: Dong-Keon
authors.initials: DK
authors.lastname: Lee
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Soochan
authors.initials: S
authors.lastname: Bae
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Dong Goo
authors.initials: DG
authors.lastname: Kang
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Qingen
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sylvia S
authors.initials: SS
authors.lastname: Singh
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea.
authors.forename: Kwon-Soo
authors.initials: KS
authors.lastname: Ha
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-752, South Korea.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
authors.affiliation: Department of BIN Fusion Technology, Chonbuk National University, Jeonju, Chonbuk 561-756, South Korea.
authors.forename: Dongwon
authors.initials: D
authors.lastname: Lee
authors.affiliation: Cardiovascular Institute, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: pkang@bidmc.harvard.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kang
authors.affiliation: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do 200-701, South Korea. Electronic address: ymkim@kangwon.ac.kr.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
mesh_terms: D000818:Animals; D001592:Benzyl Alcohols / Q000008:administration & dosage* / Q000494:pharmacology; D001775:Blood Circulation; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000235:genetics; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000235:genetics
chemical_list: D001592:Benzyl Alcohols; C018966:4-hydroxybenzyl alcohol; D052250:Nitric Oxide Synthase Type III; D051547:Heme Oxygenase-1
keywords: Angiogenesis; Biodegradable nanoparticle; Blood flow; HPOX; Hindlimb ischemia