Losartan reverses COX-2-dependent vascular dysfunction in offspring of hyperglycaemic rats

Area of Science:

• Cardiovascular Physiology
• Endocrinology
• Pharmacology

Background:

• Maternal hyperglycemia during pregnancy can lead to long-term vascular dysfunction in offspring.
• This dysfunction involves altered cyclooxygenase-2 (COX-2) activity and imbalances in vascular tone regulation.
• Angiotensin II signaling via the AT1 receptor is implicated in mediating these detrimental effects.

Purpose of the Study:

• To investigate if chronic losartan treatment, an AT1 receptor antagonist, can reverse COX-2-mediated vascular dysfunction.
• To assess the impact of losartan on endothelial function and vascular tone in mesenteric resistance arteries (MRA) of offspring from hyperglycaemic rats.

Main Methods:

• Male offspring from hyperglycaemic (O-DR) and normoglycaemic (O-CR) rats were treated with losartan for two months.
• Isometric tension measurements were performed on MRA using wire myography.
• COX-2 expression, thromboxane A2 (TxA2), prostaglandin E2 (PGE2), and prostaglandin F2α (PGF2α) release were quantified.

Main Results:

• Offspring of diabetic rats (O-DR) exhibited elevated blood pressure, impaired vasodilation, and enhanced vasoconstriction compared to controls (O-CR).
• Losartan treatment normalized these vascular parameters in O-DR.
• In O-DR, COX-2 expression and release of TxA2, PGE2, and PGF2α were increased; losartan treatment reduced these markers and normalized responses to COX inhibitors and tempol.

Conclusions:

• Chronic losartan administration reverses endothelial dysfunction in MRA of O-DR by normalizing COX-2 overexpression and balancing vasoactive factors.
• These findings support the therapeutic potential of AT1 receptor antagonists in mitigating hyperglycemia-induced vascular programming.
• The study suggests angiotensin II is a key mediator of vascular dysfunction programmed by prenatal hyperglycemia.