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Studies on Vasoconstriction and Cardiac Hypertrophy Controlled by α1A-Adrenergic Receptor

権, 哲源 Kwon, Chulwon 筑波大学

2020.07.22

概要

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. In 2017, more than 17 million people died because of CVDs, accounting for 31% of all reported deaths (1). The World Health Organization (WHO) defines CVDs as a group of disorders of the heart and blood vessels, including coronary artery disease and heart failure. Many signaling molecules are involved in the pathogenesis of these diseases. Above all, G-protein coupled receptors (GPCRs) are key regulators of cardiovascular function. In this study, I have focused on the function of GPCRs in circulatory systems.

Blood vessels are tubular organs found throughout the body that play an essential role in circulatory systems by transporting blood and by regulating blood pressure. Since normal vasoconstriction helps transport blood, including dissolved oxygen, nutrients, and hormones into many tissues of the body in order to maintain whole-body homeostasis, impairment of blood vessels frequently causes organ dysfunctions and results in lethal conditions.

A recent study reported that several GPCRs are expressed in the cardiovascular system and play roles in tissue homeostasis. Although GPCRs generally bind to their corresponding ligands and transmit extracellular signals into the cell interior by interacting with G proteins (2), recent studies suggested that multiple GPCRs form functional dimers that contribute to the progression of CVDs such as pre-eclampsia and age-related hypertension (3- 6). However, there have been no reports concerning the relationship between GPCR dimerization and vascular contractility.

APJ, a GPCR specific for apelin, has been the subject of intensive research by our research group to date. We have investigated the roles played by APJ in the cardiovascular system and showed that APJ overexpression in cardiomyocytes causes phenotypes similar to those associated with peripartum cardiomyopathy (7). Although APJ in vascular endothelial cells (VECs) is known to promote NO synthesis and induce vasodilation in vessels (8,9), our endothelial dysfunction model mice exhibited apelin-induced vasoconstriction when treated with NOS inhibitors (10). These results suggest that APJ in vascular smooth muscle cells (VSMCs) may constrict vessels by apelin.

Therefore, we generated VSMC-specific APJ-overexpressing (SMAAPJ) mice to demonstrate the vasoconstrictive effect in vivo. SMA-APJ mice displayed vascular constriction following apelin administration ex vivo (Fig. I-1B). We therefore discovered that APJ acts as a vasoconstrictor in VSMCs. Moreover, we noticed that APJ may functionally interact with α1Aadrenergic receptor (α1A-AR) in VSMCs. Adrenergic receptors, including nine functional subtypes, are mainly expressed in tissues of the heart, lung, kidney, and vessels, and play various roles in each tissue. In particular, the α1-subtype plays a major role in regulating blood vessel diameter, i.e. vascular tone (11). In Chapter II, I will describe my findings concerning the functional interaction between APJ and α1A-AR in vasoconstriction, by measuring vascular contractility in response to ligands ex vivo in SMAAPJ/α1A-AR-KO mice that I generated.

The incidence of CVDs differs between men and women (12), especially since pregnancy sometimes becomes a risk factor for CVDs in women. The pregnancy-associated risk arises because of hemodynamic changes, including increases in heart rate and circulating blood volume. These alterations in normal pregnancy induce physiological cardiac hypertrophy (13,14), whereas hypertensive disorders of pregnancy (HDP) frequently develop into pathological cardiac hypertrophy, which is a hallmark of progression toward heart failure (15). Whereas there are only a few studies focused on cardiac hypertrophy under HDP conditions, our research group has previously generated pregnancy-associated hypertensive mice (PAH) that exhibit physiological cardiac hypertrophy during gestation (16) (Fig. I-2).

In summary, I have elucidated novel functions of α1A-AR in APJinduced vasoconstriction. These findings provide new insights into α1A-AR in relation to CVD.

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