Prostaglandin F _2α elevates blood pressure and promotes atherosclerosis

Abstract

Little is known about prostaglandin F2␣ in cardiovascular homeostasis. Prostaglandin F2␣ dose-dependently elevates blood pressure in WT mice via activation of the F prostanoid (FP) receptor. The FP is expressed in preglomerular arterioles, renal collecting ducts, and the hypothalamus. Deletion of the FP reduces blood pressure, coincident with a reduction in plasma renin concentration, angiotensin, and aldosterone, despite a compensatory upregulation of AT1 receptors and an augmented hypertensive response to infused angiotensin II. Plasma and urinary osmolality are decreased in FP KOs that exhibit mild polyuria and polydipsia. Atherogenesis is retarded by deletion of the FP, despite the absence of detectable receptor expression in aorta or in atherosclerotic lesions in Ldlr KOs. Although vascular TNF ␣, inducible nitric oxide enzyme and TGF ␤ are reduced and lesional macrophages are depleted in the FP/Ldlr double KOs, this result reflects the reduction in lesion burden, as the FP is not expressed on macrophages and its deletion does not alter macrophage cytokine generation. Blockade of the FP offers an approach to the treatment of hypertension and its attendant systemic vascular disease.hypertension ͉ renin ͉ PGF2␣ receptor ͉ juxtaglomerular granular cell ͉ water metabolism C ontrol of hypertension has contributed to a decline of cardiovascular morbidity and mortality. Therapies have targeted neurohumoral mechanisms, such as the sympathoadrenal and renin-angiotensin-aldosterone systems (RAAS) as well as downstream effectors and volume control. Elevated blood pressure (BP) cosegregates with clinical cardiovascular events and randomized trials have revealed the efficacy of antihypertensive drugs to reduce the risk of stroke and myocardial infarction (1). Angiotensin II activates and up-regulates NADPH oxidase (2), augmenting oxidant stress and vascular dysfunction. Both pharmacological and genetic disruption of elements of the RAAS decreases BP and retards atherogenesis (3-5).Prostaglandins (PGs) also contribute to BP homeostasis. Elevation of BP complicates the use of nonsteroidal antiinflammatory drugs and relates to the degree of inhibition of cyclooxygenase (COX)-2 and the selectivity with which it is attained (6). Genetic and pharmacological manipulations suggest that products of COX-1 may elevate BP (7), although the impact of manipulating the PG cascade is conditioned by genetic background in mice (8). Prostacyclin (PGI 2 ) is a potent renin secretagogue (9), and its biosynthesis is increased markedly in pregnancy, a high-renin but hypotensive condition; its biosynthesis is depressed in pregnancy-induced hypertension (10). Deletion of its I prostanoid receptor (the IP) reduces BP in renoprival models of high-renin hypertension in rodents (11). PGI 2 is also a vasodilator and promotes sodium excretion; indeed, salt-sensitive hypertension characterizes IP-KO mice in some genetic backgrounds (12). PGF 2␣ is derived mainly from COX-1 in the female reproductive system, where it is required for normal parturition ...

Angiotensin II Type I and Prostaglandin F2α Receptors Cooperatively Modulate Signaling in Vascular Smooth Muscle Cells

“…Interestingly, the pressor effect of Ang II was potentiated in FP knock-out animals (9) suggesting that basal interactions are important for establishing physiological parameters as for the ghrelin receptor/D2-dopamine receptor pair. We observed asymmetric effects on ligand binding as the presence of AT1R altered the affinity of PGF2␣ for FP but not the converse.…”

“…Several groups (including us) have shown that FP activates ERK1/2 in HEK 293 cells via the G␣ q -PKC pathway (5)(6)(7) and that this response was modulated by both biased allosteric and orthosteric ligands (5,8). FP has been shown to be involved in blood pressure regulation by the angiotensin II (Ang II) type 1 receptor (AT1R) (9). AT1R plays a critical role in vascular remodeling and is part of the renin-angiotensin system, a key regulator of blood pressure, electrolyte balance, and numerous neuronal and endocrine actions associated with cardiovascular function.…”

Blood Pressure Elevation Associated with Topical Prostaglandin F2α Analogs: An Analysis of the Different Spontaneous Adverse Event Report Databases

“…5,6) Some studies have reported the ability of PGF2α to elevate blood pressure. 7,8) Although some clinical trials have reported that topical PGF2α analogs are safe, [9][10][11] they are thought to cause systemic adverse events. Some examples include ophthalmic timolol or brimonidine, which reduce systemic blood pressure by β-receptor blocking [12][13][14] or α-receptor stimulating actions.…”

New axis in hypertension

“…1 Now that the receptor has been shown to be involved in the renin-angiotensin system, it offers a new way to attack a pathway that has already yielded multiple marketed drugs.Depression of the renin-angiotensin system (RAS) is known to decrease systemic blood pressure and slow atherogenesis, the formation of atherosclerotic plaques. 2 Although signaling through the prostaglandin E 2 receptor (PTGER4; PGE 2 ) and the prostacyclin receptor (PTGIR; IP; PGI2) is known to modulate this pathway, 3,4 the role of the prostaglandin F receptor (PTGFR; FP) has been less clear.…”

“…1 Now that the receptor has been shown to be involved in the renin-angiotensin system, it offers a new way to attack a pathway that has already yielded multiple marketed drugs.…”