Periadventitial adipose tissue modulates the effect of PROLI/NO on neointimal hyperplasia.
Periadventitial delivery of nitric oxide (NO) inhibits neointimal hyperplasia; however, the effect of periadventitial adipose tissue on the efficacy of NO at inhibiting neointimal hyperplasia has not been studied. The aim of our study was to assess the effect of NO in the presence and absence of periadventitial adipose tissue. We hypothesized that removal of periadventitial adipose tissue will increase neointimal formation and that NO will be more effective at inhibiting neointimal hyperplasia.



The effect of NO on 3T3 fibroblasts, adventitial fibroblast (AF), and vascular smooth muscle cell (VSMC) proliferation was assessed by (3)H-thymidine incorporation in adipocyte-conditioned or regular media. The rat carotid artery balloon injury model was performed on male Sprague-Dawley rats. Before balloon injury, periadventitial adipose tissue was removed (excised model) or remained intact (intact model). Treatment groups included injury or injury with periadventitial application of PROLI/NO. Adiponectin receptor (AR) levels were assessed via immunofluorescence.



Adipocyte-conditioned media had an antiproliferative effect on 3T3 and AF and a proproliferative effect on VSMC in vitro. Interestingly, NO was less effective at inhibiting 3T3 and AF proliferation and more effective at inhibiting VSMC proliferation in adipocyte-conditioned media. In vivo, the excised group showed increased neointimal hyperplasia 2 wk after surgery compared with the intact group. NO reduced neointimal hyperplasia to a greater extent in the excised group compared with the intact group. Although NO inhibited or had no impact on AR levels in the intact group, NO increased AR levels in media and adventitia of the excised group.



These data show that periadventitial adipose tissue plays a role in regulating the arterial injury response and the efficacy of NO treatment in the vasculature.
Division of Vascular Surgery, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
Edward S M
ESM
Bahnson
Division of Vascular Surgery, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
George E
GE
Havelka
Division of Vascular Surgery, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
Nathaniel C
NC
Koo
Division of Vascular Surgery, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois.
Qun
Q
Jiang
Division of Vascular Surgery, Northwestern University, Chicago, Illinois; Simpson Querrey Institute for BioNanotechnology, Northwestern University, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois. Electronic address: mkibbe@northwestern.edu.
Melina R
MR
Kibbe
D016475:3T3 Cells; D052436:Adipose Tissue, White / Q000503:physiopathology* / Q000601:surgery; D063194:Adventitia; D000818:Animals; D020212:Carotid Artery Injuries / Q000150:complications* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D006965:Hyperplasia; D015187:Lipectomy; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D058426:Neointima / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000494:pharmacology / Q000627:therapeutic use; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D020011:Protective Agents; C102043:proline-nitric oxide; D009569:Nitric Oxide; D011392:Proline
Adipokines; Neointimal hyperplasia; Nitric oxide; Periadventitial adipose tissue
Free Radic Biol Med. 2008 Jan 1;44(1):73-81
18045549
J Vasc Surg. 2010 May;51(5):1248-59
20223627
J Cardiovasc Pharmacol. 1989;14 Suppl 6:S12-15
2478818
PLoS One. 2014 Aug 12;9(8):e103587
25116394
Circulation. 1996 Oct 1;94(7):1655-64
8840858
Circ Cardiovasc Qual Outcomes. 2008 Sep;1(1):38-45
20031786
J Vasc Surg. 1986 Jun;3(6):877-84
3712635
Circ Res. 2009 Oct 23;105(9):906-11
19762682
PLoS One. 2011;6(5):e20540
21637782
Proc Natl Acad Sci U S A. 1991 May 1;88(9):3739-43
2023924
Arterioscler Thromb Vasc Biol. 2010 Aug;30(8):1576-82
20489168
Circulation. 2012 Jan 3;125(1):e2-e220
22179539
Antioxid Redox Signal. 2016 Mar 10;24(8):401-18
26593400
Circulation. 2003 Mar 11;107(9):1271-7
12628947
Nitric Oxide. 2011 Jun 30;25(1):22-30
21554972
Arterioscler Thromb Vasc Biol. 2013 May;33(5):980-7
23520165
Med Hypotheses. 2008;70(5):1044-7
17910991
Nitric Oxide. 2015 Jan 30;44:8-17
25460325
Cell Biochem Biophys. 2011 Jun;60(1-2):89-97
21448667
J Surg Res. 2013 Mar;180(1):35-42
23164361
Trends Endocrinol Metab. 2002 Mar;13(2):84-9
11854024
Free Radic Biol Med. 2016 Jan;90:272-86
26627935