Heterogeneous distribution of angiotensin I-converting enzyme (CD143) in the human and rat vascular systems: Vessel, organ and species specificity

Abstract

Angiotensin I-converting enzyme (kininase II, ACE, CD143) availability is a determinant of local angiotensin and kinin concentrations and physiological actions. Limited information is available on ACE synthesis in peripheral vascular beds. We studied the distribution of ACE along the human and rat vascular tree, and determined whether the enzyme was uniformly distributed in all endothelial cells (EC) or if differences occurred among vessels and organs.

The distribution of ACE was assessed by using a panel of anti-human ACE monoclonal antibodies and serial sections of the entire vascular tree of humans. Comparison was made with other EC markers. EC of small muscular arteries and arterioles displayed high ACE immunoreactivity in all organs studied except the kidney, while EC of large arteries and of veins were poorly reactive or completely negative. Only 20% on average of capillary EC in each organ, including the heart, stained for ACE, with the remarkable exception of the lung and kidney. In the lung all capillary EC were labeled intensively for ACE, whereas in the kidney the entire vasculature was devoid of detectable enzyme. In contrast to the man, the rat showed homogeneous endothelial expression of ACE in all large and middle-sized arteries, and in veins, but in renal vessels ACE expression was reduced.

This study documents a vessel, organ and species specific pattern of distribution of endothelial ACE. The markedly reduced ACE content of the renal vasculature may protect the renal circulation against excess angiotensin II formation and kinin depletion, and maintain high renal blood flow.

Introduction

The angiotensin I-converting enzyme (dipeptidylcarboxypeptidase I, kininase II, EC 3.4.15.1, CD143, ACE) is a transmembrane ectopeptidase of vascular endothelial cells (EC), also secreted as a so called soluble form in plasma. This enzyme plays an important role in cardiovascular homeostasis through the generation of angiotensin II from angiotensin I and the inactivation of kinins (Skeggs et al., 1956, Erdos, 1990). Numerous studies using ACE inhibitors indicate that ACE participates in the control of vascular tone and blood pressure, especially in situations where renin secretion, and therefore angiotensin I production are stimulated, and in organs where kinins are released (Cushman and Ondetti, 1980, Unger and Gohlke, 1994). In pathological situations however, high angiotensin II formation, and kinin depletion can be deleterious for the cardiovascular system and the kidney (Alhenc-Gelas and Corvol, 2000, Dzau et al., 2001). Hence, clinical and experimental studies have linked genetically determined ACE level to onset and progression of cardiovascular and renal diseases (Cambien et al., 1992, Marre et al., 1994, Sayed-Tabatabaei et al., 2006, Krege et al., 1995, Huang et al., 2001, Bernstein et al., 2005, Messadi et al., 2010).

The ACE gene is constitutionally expressed in vascular EC where early works located the enzyme to the luminal plasma membrane of these cells in lung capillaries and large vessels of several animal species (Caldwell et al., 1976, Ryan et al., 1976). While ACE activity is also detected in the vascular smooth muscle, at least in the rat aorta, and in the adventitia, the main source of ACE in arteries is the endothelium (Arnal et al., 1994, Rogerson et al., 1992).

ACE activity or mRNA has been detected in vessels or cultured EC from several animal or human fetal or adult sources, but usually in low amounts (Johnson et al., 1980, Schutz et al., 1996, Balyasnikova et al., 1998), and no reliable comparison among sources is feasible. In man ACE has been detected by immunohistochemistry in the lung and in small arteries and capillaries of a few studied organs (Takada et al., 1981, Bruneval et al., 1986, Danilov et al., 1987, Mounier et al., 1987, Sibony et al., 1993) but no systematic study of the distribution of ACE in the vascular system has been carried out. It is therefore not known whether endothelial ACE is uniformly distributed along the arterial tree and capillary network, or if differences occur among vessels and organs.

Theoretical and experimental evidence suggests that ACE levels in plasma and in vessels of peripheral organs is an important determinant of local angiotensin and kinin concentrations, especially in the heart and kidney, and is involved in progression of diseases affecting these organs (Huang et al., 2001, Messadi et al., 2010, Takahashi et al., 2003). These considerations prompted us to examine by immunohistochemistry and immune electron microscopy the distribution of ACE, assigned to CD143 along the human vascular tree (Danilov et al., 1997). Comparison was made with the rat vascular system, where ACE distribution remained also largely unknown. We observed a very heterogeneous pattern of ACE distribution in EC of the human vascular system, with large differences in the abundance of the enzyme among the different vessel types, and also among vascular territories. These observations may have physiological and pathological implications.