PMID- 29162746
OWN - NLM
STAT- MEDLINE
DCOM- 20190211
LR  - 20190215
IS  - 1470-8736 (Electronic)
IS  - 0143-5221 (Linking)
VI  - 132
IP  - 1
DP  - 2018 Jan 16
TI  - Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is 
      dependent on constrictor prostanoid activity and Y chromosome lineage.
PG  - 131-143
LID - 10.1042/CS20171291 [doi]
AB  - Vascular dysfunction is a hallmark of hypertension and the strongest risk factor 
      to date for coronary artery disease. As Y chromosome lineage has emerged as one 
      of the strongest genetic predictors of cardiovascular disease risk to date, we 
      investigated if Y chromosome lineage modulated this important facet in the 
      stroke-prone spontaneously hypertensive rat (SHRSP) using consomic strains. Here, 
      we show that vascular dysfunction in the SHRSP is attributable to differential 
      cyclooxygenase (COX) activity with nitric oxide (NO) levels playing a less 
      significant role. Measurement of prostacyclin, the most abundant product of COX 
      in the vasculature, confirmed the augmented COX activity in the SHRSP aorta. This 
      was accompanied by functional impairment of the vasodilatory prostacyclin (IP) 
      receptor, while inhibition of the thromboxane (TP) receptor significantly 
      ameliorated vascular dysfunction in the SHRSP, suggesting this is the downstream 
      target responsible for constrictor prostanoid activity. Importantly, Y chromosome 
      lineage was shown to modulate vascular function in the SHRSP through influencing 
      COX activity, prostacyclin levels and IP dysfunction. Vascular dysfunction in the 
      renal and intrarenal arteries was also found to be prostanoid and Y chromosome 
      dependent. Interestingly, despite no apparent differences in agonist-stimulated 
      NO levels, basal NO levels were compromised in the SHRSP aorta, which was also Y 
      chromosome dependent. Thus, in contrast with the widely held view that COX 
      inhibition is deleterious for the vasculature due to inhibition of the 
      vasodilator prostacyclin, we show that COX inhibition abolishes vascular 
      dysfunction in three distinct vascular beds, with IP dysfunction likely being a 
      key mechanism underlying this effect. We also delineate a novel role for Y 
      chromosome lineage in regulating vascular function through modulation of COX and 
      basal NO levels.
CI  - (c) 2018 The Author(s). Published by Portland Press Limited on behalf of the 
      Biochemical Society.
FAU - Khan, Shanzana I
AU  - Khan SI
AD  - Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery 
      Institute, Monash University, Melbourne, Victoria, Australia 
      shanzana.khan@monash.edu.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
AD  - Department of Medicine, Monash University, Melbourne, Victoria, Australia.
FAU - Andrews, Karen L
AU  - Andrews KL
AD  - Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery 
      Institute, Monash University, Melbourne, Victoria, Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
FAU - Jefferis, Ann-Maree
AU  - Jefferis AM
AD  - Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery 
      Institute, Monash University, Melbourne, Victoria, Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
FAU - Jennings, Garry L
AU  - Jennings GL
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
AD  - Sydney Medical School, University of Sydney, Camperdown, New South Wales, 
      Australia.
FAU - Sampson, Amanda K
AU  - Sampson AK
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
FAU - Chin-Dusting, Jaye P F
AU  - Chin-Dusting JPF
AD  - Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery 
      Institute, Monash University, Melbourne, Victoria, Australia.
AD  - Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180116
PL  - England
TA  - Clin Sci (Lond)
JT  - Clinical science (London, England : 1979)
JID - 7905731
RN  - 0 (Prostaglandins)
RN  - 0 (Vasodilator Agents)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - EC 1.14.99.1 (Prostaglandin-Endoperoxide Synthases)
RN  - N9YNS0M02X (Acetylcholine)
SB  - IM
MH  - Acetylcholine/pharmacology
MH  - Animals
MH  - Aorta/metabolism/*physiopathology
MH  - Endothelium, Vascular/metabolism/physiopathology
MH  - Hypertension/genetics/*physiopathology
MH  - Male
MH  - Nitric Oxide/metabolism
MH  - Prostaglandin-Endoperoxide Synthases/metabolism
MH  - Prostaglandins/*metabolism
MH  - Rats, Inbred SHR
MH  - Rats, Inbred WKY
MH  - Stroke/genetics/*physiopathology
MH  - Vasodilation/drug effects
MH  - Vasodilator Agents/pharmacology
MH  - *Y Chromosome
OTO - NOTNLM
OT  - TP receptor
OT  - Y chromosome
OT  - cyclooxygenase
OT  - hypertension pathology
OT  - vascular function
EDAT- 2017/11/23 06:00
MHDA- 2019/02/12 06:00
CRDT- 2017/11/23 06:00
PHST- 2017/08/20 00:00 [received]
PHST- 2017/11/13 00:00 [revised]
PHST- 2017/11/17 00:00 [accepted]
PHST- 2017/11/23 06:00 [pubmed]
PHST- 2019/02/12 06:00 [medline]
PHST- 2017/11/23 06:00 [entrez]
AID - CS20171291 [pii]
AID - 10.1042/CS20171291 [doi]
PST - epublish
SO  - Clin Sci (Lond). 2018 Jan 16;132(1):131-143. doi: 10.1042/CS20171291. Print 2018 
      Jan 16.