Vasodilation to PTH (1-84) in bone arteries is dependent upon the vascular endothelium and is mediated partially via VEGF signaling.
BACKGROUND
Intermittent PTH administration directly stimulates osteoblasts; however, mechanisms of bone accrual that are independent of the direct actions on osteoblasts may be under-appreciated. Our aims were to decipher (1) whether PTH 1-84 augments vasodilation of the femoral principal nutrient artery (PNA), (2) whether 15 days of intermittent PTH 1-84 augments endothelium-dependent and/or -independent vasodilation of the femoral PNA, and (3) the signaling mechanisms involved.


METHODS
Experiment 1: Femoral PNAs from male Wistar rats were exposed to cumulative doses of PTH 1-84 with and without an anti-vascular endothelial growth factor antibody and/or the endothelial NO synthase inhibitor l-NAME. Experiment 2: Male Wistar rats were administered PTH and/or the anti-VEGF antibody for 2 weeks. Subsequently, endothelium-dependent vasodilation to acetylcholine and endothelium-independent vasodilation to sodium nitroprusside were assessed. In addition, endothelium-dependent signaling pathways were analyzed by use of l-NAME and/or and the cyclooxygenase inhibitor indomethacin.


RESULTS
Cumulative doses of PTH 1-84 induced vasodilation of the femoral PNA, which was reduced by 38% and 87% with the anti-VEGF antibody and l-NAME, respectively. Secondly, 2 weeks of intermittent PTH 1-84 administration doubled trabecular bone volume, augmented bone formation parameters and reduced osteoclast activity. In addition, PTH enhanced endothelium-dependent vasodilation via up-regulation of NO. Co-administration of the anti-VEGF antibody (1) inhibited the PTH-induced increase in bone volume and remodeling parameters and (2) blunted the augmented vasodilator responsiveness of the PNA. Finally, endothelium-dependent vasodilation in PTH-treated rats was highly correlated with trabecular bone volume.


CONCLUSIONS
As hypothesized, PTH enhanced endothelium-dependent vasodilation of the femoral PNA via augmented NO production and was mediated partially through VEGF signaling. Further, vasodilation to PTH appears independent of vascular smooth muscle cell participation. More importantly, the strong association between vasodilation and bone volume suggests that bone arteriolar function is critical for PTH-induced bone anabolism.
Department of Kinesiology and Applied Physiology, University of Delaware, Newark, DE 19716, USA. prisby@UDel.Edu
Rhonda
R
Prisby
Thomas
T
Menezes
Jeremiah
J
Campbell
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology; D001158:Arteries / Q000502:physiology*; D001696:Biomechanical Phenomena / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D005269:Femur / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology
D000906:Antibodies; D016861:Cyclooxygenase Inhibitors; D010281:Parathyroid Hormone; D042461:Vascular Endothelial Growth Factor A; D014665:Vasodilator Agents; D009599:Nitroprusside; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D019331:NG-Nitroarginine Methyl Ester