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Reduced bioavailability of tetrahydrobiopterin impairs neovascularization after hind limb ischemia
Author(s) -
Santhanam Anantha Vijay R,
d'Uscio Livius V,
Smith Leslie A,
Katusic Zvonimir S
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.754.3
Subject(s) - tetrahydrobiopterin , angiogenesis , endocrinology , medicine , neovascularization , bone marrow , arteriogenesis , ischemia , progenitor cell , hindlimb , chemistry , nitric oxide , nitric oxide synthase , biology , stem cell , microbiology and biotechnology
Impaired endothelial function in cardiovascular disorders is mediated, in part, by uncoupling of eNOS caused by reduced availability of tetrahydrobiopterin (BH 4 ). Endothelial progenitor cells (EPCs), originating from bone marrow, contribute to repair of vascular system by either neovascularization following tissue ischemia or re‐endothelialization after endothelial injury. The contribution of BH 4 to the angiogenic function has not been studied. In the present study, we investigated the role of BH 4 in angiogenesis and mobilization of cells enriched in EPCs in hph‐1 mutant mice, a genetic model of GTP‐cyclohydrolase I deficiency. HPLC analysis revealed that enzymatic activity of GTP‐cyclohydrolase I is reduced by 65% in bone marrow of hph‐1 mice (22±4 pmol neopterin/mg/h; P<0.05 vs. wild‐type mice: 63±4 pmol/mg/h). Basal counts of cells co‐expressing CD34 and VEGFR2 (Flk‐1) were reduced in bone marrow and peripheral blood of hph‐1 mice. Fourteen days after hind limb ischemia, recovery of blood flow was significantly reduced in hph‐1 mice as compared to blood flow in ischemic limb of wild type mice. Our findings suggest that reduced bioavailability of BH 4 impairs mobilization of cells enriched in EPCs. This effect may help to explain impaired angiogenesis in hph‐1 mice.