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Prostaglandin F2 Elevates Blood Pressure and Promotes Prostaglandin F2␣ elevates blood pressure and promotes atherosclerosis Ying Yua,1, Margaret B. Lucitta,1, Jane Stubbea, Yan Chenga, Ulla G. Friisb, Pernille B. Hansenb, Boye L. Jensenb, Emer M. Smytha, and Garret A. FitzGeralda,2 aInstitute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA 19104; and bDepartment of Physiology and Pharmacology, University of Southern Denmark-Odense, DK-5000 Odense C, Denmark Edited by Bengt Samuelsson, Karolinska Institutet, Stockholm, Sweden, and approved March 26, 2009 (received for review November 20, 2008) Little is known about prostaglandin F2␣ in cardiovascular ho- convoluted tubules and cortical collecting ducts (CCD) (14). meostasis. Prostaglandin F2␣ dose-dependently elevates blood Renal elaboration of PGF2␣ is augmented by salt (15), and pressure in WT mice via activation of the F prostanoid (FP) receptor. activation of the FP modulates water absorption in the collecting The FP is expressed in preglomerular arterioles, renal collecting ducts in vitro by inhibiting the action of vasopressin (15). Both ducts, and the hypothalamus. Deletion of the FP reduces blood PGF2␣ and thromboxane A2 mediate lipopolysaccharide- pressure, coincident with a reduction in plasma renin concentra- induced tachycardia (16). However, the importance of PGF2␣ in tion, angiotensin, and aldosterone, despite a compensatory up- vivo in fluid/electrolyte homeostasis and BP regulation remains regulation of AT1 receptors and an augmented hypertensive re- to be defined. sponse to infused angiotensin II. Plasma and urinary osmolality are In the present study, we determine that PGF2␣ elevates BP, decreased in FP KOs that exhibit mild polyuria and polydipsia. accelerates atherosclerosis, and restrains water intake in rodents. Atherogenesis is retarded by deletion of the FP, despite the This result occurs despite the absence of detectable FP expres- absence of detectable receptor expression in aorta or in athero- sion in normal aorta or atherosclerotic lesions. Antagonists of sclerotic lesions in Ldlr KOs. Although vascular TNF␣, inducible the FP, mechanistically distinct from direct renin inhibitors (5, nitric oxide enzyme and TGF␤ are reduced and lesional macro- 17), may emerge as therapies in the treatment of both hyper- phages are depleted in the FP/Ldlr double KOs, this result reflects tension and its attendant vascular disease. the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine Results ؊ ؊ generation. Blockade of the FP offers an approach to the treatment BP Is Reduced and the RAAS Is Depressed in FP / Mice. The effect of hypertension and its attendant systemic vascular disease. of FP deficiency on BP in normolipidemic (both on normal chow and following salt depletion) and hyperlipidemic (LdlrϪ/Ϫ/ Ϫ/Ϫ hypertension ͉ renin ͉ PGF2␣ receptor ͉ juxtaglomerular granular cell ͉ FP ) mice was assessed by both tail-cuff measurement and water metabolism telemetry. Resting systolic pressure was lower in normolipidemic FPϪ/Ϫ mice (normal diet, 109.8 mm Hg Ϯ 3.3, n ϭ 11; salt depletion, 107.7 mm Hg Ϯ 3.4, n ϭ 11) compared with WT ontrol of hypertension has contributed to a decline of controls (normal diet, 125.3 mm Hg Ϯ 3.2, n ϭ 11; P Ͻ 0.001; cardiovascular morbidity and mortality. Therapies have tar- C salt depletion, 121.0 mm Hg Ϯ 3.3, n ϭ 16; P Ͻ 0.01) (Fig. 1A) geted neurohumoral mechanisms, such as the sympathoadrenal Ϫ Ϫ Ϫ Ϫ and in hyperlipidemic Ldlr / /FP / mice [103.3 mm Hg Ϯ 3.26, and renin-angiotensin-aldosterone systems (RAAS) as well as n ϭ 16, 12 weeks high-fat diet (HFD); 115.2 mm Hg Ϯ 1.53, n ϭ downstream effectors and volume control. Elevated blood pres- Ϫ Ϫ 16, 24 weeks HFD] compared with Ldlr / controls (120.1 mm sure (BP) cosegregates with clinical cardiovascular events and Hg Ϯ 3.16, n ϭ 16, P Ͻ 0.0001, 12 weeks HFD; 124.2 mm Hg Ϯ randomized trials have revealed the efficacy of antihypertensive 3.18, n ϭ 16, P Ͻ 0.05, 24 weeks HFD) (Fig. 1 B and C). The drugs to reduce the risk of stroke and myocardial infarction (1). difference in BP between FPϪ/Ϫ mice and controls was sustained Angiotensin II activates and up-regulates NADPH oxidase (2), throughout the 24-h period in the telemetric studies. Tachycar- augmenting oxidant stress and vascular dysfunction. Both phar- dia, reactive to hypotension, did not differ between the groups. macological and genetic disruption of elements of the RAAS Neither BP nor heart rate differed between normolipidemic and decreases BP and retards atherogenesis (3–5). hyperlipidemic mice. Prostaglandins (PGs) also contribute to BP homeostasis. Elevation of BP complicates the use of nonsteroidal anti- Deletion of the FP Depressed Plasma Renin, Angiotensin I, and inflammatory drugs and relates to the degree of inhibition of Aldosterone Concentrations. Salt depletion activated the RAAS cyclooxygenase (COX)-2 and the selectivity with which it is and exacerbated the impact of FP deletion on plasma renin MEDICAL SCIENCES attained (6). Genetic and pharmacological manipulations sug- concentration and on angiotensin I (Fig. 1 D and E), but not gest that products of COX-1 may elevate BP (7), although the aldosterone secretion (Fig. 1F), suggesting that other angioten- impact of manipulating the PG cascade is conditioned by genetic sin-independent factors (e.g., adrenergic control) may be in- background in mice (8). Prostacyclin (PGI2) is a potent renin volved in the regulation of aldosterone secretion in response to secretagogue (9), and its biosynthesis is increased markedly in pregnancy, a high-renin but hypotensive condition; its biosyn- thesis is depressed in pregnancy-induced hypertension (10). Author contributions: Y.Y., M.B.L., and G.A.F. designed research; Y.Y., M.B.L., J.S., Y.C., Deletion of its I prostanoid receptor (the IP) reduces BP in U.G.F., P.B.H., B.L.J., and E.M.S. performed research; Y.Y. and M.B.L. analyzed data; and renoprival models of high-renin hypertension in rodents (11). Y.Y., M.B.L., and G.A.F. wrote the paper. The authors declare no conflict of interest. PGI2 is also a vasodilator and promotes sodium excretion; indeed, salt-sensitive hypertension characterizes IP-KO mice in This article is a PNAS Direct Submission. some genetic backgrounds (12). Freely available online through the PNAS open access option. PGF2␣ is derived mainly from COX-1 in the female repro- 1Y.Y. and M.B.L. contributed equally to this work. ductive system, where it is required for normal parturition in 2To whom correspondence should be addressed. E-mail: [email protected]. mice (13, 14). The F prostanoid receptor (the FP) is also This article contains supporting information online at www.pnas.org/cgi/content/full/ expressed abundantly in the kidney, particularly in the distal 0811834106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0811834106 PNAS ͉ May 12, 2009 ͉ vol. 106 ͉ no. 19 ͉ 7985–7990 Downloaded by guest on September 26, 2021 -/- A B Ldlr C Ldlr -/- A B 6 140 WT -/- -/- 140 Ldlr / FP 140 Ldlr -/- / FP -/- FP-/- 20 * 5 130 120 120 * *** RNA) 100 100 120 15 4 * * 80 80 11 0 / 18s r 7 3 60 60 / 18s rRNA) 7 10 SBP mmHg SBP SBP mmHg SBP 100 mmHg SBP 40 40 X10 2 90 20 20 5 1 80 0 0 Normal Diet Salt depletion 12 wks 12 wks 24 wks 24 wks AT1b ( AT1a ( X10 ( AT1a 0 0 WT FP-/- WT FP-/- D E F200 20 0.20 WT WT WT -/- -/- FP FP FP -/- C 60 15 WT 0.15 150 -/- * 50 FP 10 PRC * * 0.10 PAC (pg/ml)100 40 5 * (ng Ang I/ml/h) * * Plasma Ang Ang Plasma I (ng /ml) 0.05 30 0 50 Normal Diet Salt depletion Normal Diet Salt depletion Normal Diet Salt depletion 20 Fig. 1. Deletion of FP reduces BP and decreases renin-angiotensin- aldosterone concentration. Systolic BP (SBP) measurements in (A)FPϪ/Ϫ mice 10 Ϫ/Ϫ Ϫ/Ϫ on a normal chow diet and after salt depletion by tail cuff and Ldlr /FP on 0 HFD for either (B) 12 weeks by tail cuff or (C) 24 weeks by radiotelemetry. 123456789 Values represent mean Ϯ SEMs analyzed by unpaired Student t test. *, P Ͻ 0.05 pressure blood in Change -10 Time (min) versus WT controls (n ϭ 11–16), *, P Ͻ 0.05, ***, P Ͻ 0.0001 versus LdlrϪ/Ϫ Ang II controls (n ϭ 16–18). (D) Plasma renin concentration (PRC), (E) plasma angio- Ϫ/Ϫ tensinogen I concentration, and (F) plasma aldosterone concentration (PAC) in Fig. 2. Elevated pressor response mediated by angiotensin II in FP mice FPϪ/Ϫ mice under normal and salt-depleted conditions. For salt depletion, mice with up-regulated expression of AT1 gene in aorta. (A) AT1a and (B) AT1b Ͻ ϭ were subjected to a low-salt diet (0.12% NaCl) and injected with furosemide gene expression in aorta by real-time RT-PCR. *, P 0.01 (n 4) versus WT, (25 mg/kg i.p.) every day. Values represent mean Ϯ SEMs analyzed by unpaired repeated 3 times. (C) BP change after angiotensin II (Ang II) administration (50 Ϫ/Ϫ Student t test. *, P Ͻ 0.05 versus WT control mice (n ϭ 6–9). ng/kg) compared with baseline in FP and WT litter mates. Mean arterial BP was monitored in mice by pressure transducer connected to a catheter in left artery. Baseline BP is readout before injection. BP changes are depicted as the Ͻ salt depletion (18). Similar results were obtained in hyperlipid- difference between baseline and after injection at 1-min intervals.
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