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.
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Research Article|
January 16 2018
Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage
Shanzana I. Khan;
1Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
2Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
3Department of Medicine, Monash University, Melbourne, Victoria, Australia
Correspondence: Shanzana I. Khan (shanzana.khan@monash.edu)
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Karen L. Andrews;
Karen L. Andrews
1Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
2Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
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Ann-Maree Jefferis;
Ann-Maree Jefferis
1Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
2Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
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Garry L. Jennings;
Garry L. Jennings
2Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
4Sydney Medical School, University of Sydney, Camperdown, New South Wales, Australia
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Amanda K. Sampson;
Amanda K. Sampson
*
2Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
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Jaye P.F. Chin-Dusting
Jaye P.F. Chin-Dusting
*
1Cardiovascular Disease Program, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
2Baker Heart and Diabetes Institute, Melbourne, Victoria, 3004, Australia
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Clin Sci (Lond) (2018) 132 (1): 131–143.
Article history
Received:
August 20 2017
Revision Received:
November 13 2017
Accepted:
November 17 2017
Accepted Manuscript online:
November 21 2017
Citation
Shanzana I. Khan, Karen L. Andrews, Ann-Maree Jefferis, Garry L. Jennings, Amanda K. Sampson, Jaye P.F. Chin-Dusting; Vascular dysfunction in the stroke-prone spontaneously hypertensive rat is dependent on constrictor prostanoid activity and Y chromosome lineage. Clin Sci (Lond) 16 January 2018; 132 (1): 131–143. doi: https://doi.org/10.1042/CS20171291
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