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Background: The participation of endothelin-1 (ET-1) in the control of vascular tone in humans has been questioned, on the basis of the finding of subthreshold immunoreactive (ir) ET-1 plasma levels. However, because most ET-1 is secreted abluminally, it might attain a higher concentration in the tunica media than in plasma. Furthermore, evidence indicates that vascular smooth muscle cells (VSMCs) can synthesize ET-1 on stimulation in vitro. We therefore looked for irET-1 in the different layers of the wall of human arteries, including renal, gastric, and internal thoracic artery wall, obtained ex vivo from consenting patients with coronary artery disease and/or high blood pressure undergoing surgery, as well as from young organ donors., Methods and Results: We performed immunohistochemistry with specific anti-ET-1 and anti-vWF antibodies followed by detection with an avidin-biotin complex ultrasensitive kit. The presence of preproET-1 and human endothelin-converting enzyme-1 (hECE-1) mRNA was also investigated by reverse transcription-polymerase chain reaction in homogenates of vessel wall, including preparations deprived of both endothelium and adventitia, and in isolated VSMCs. We detected irET-1 in the endothelium of all arteries and in the tunica media of internal thoracic artery from most patients with coronary artery disease. PreproET-1 and hECE-1 mRNA was also detected in VSMCs isolated from these vessels. irET-1 and irvWF staining in endothelium and tunica media was measured by use of microscope-coupled computer-assisted technology. Significant correlations between the amount of irET-1 in the tunica media and mean blood pressure (P<0.05), total serum cholesterol (P<0.05), and number of atherosclerotic sites (P<0.001) were found. Thus, in organ donors, irET-1 was detectable almost exclusively in endothelial cells, whereas in patients with coronary artery disease and/or arterial hypertension, sizable amounts of irET-1 were detectable in the tunica media of different types of arteries. In addition, VSMCs isolated from these vessels coexpressed the preproET-1 and hECE-1 genes., Conclusions: Collectively, these findings are consistent with the contention that endothelial damage occurs in most patients with atherosclerosis and/or hypertension and that ET-1 is synthesized in VSMCs of these patients.

Background: Since hyperaldosteronism has been experimentally related to myocardial interstitial fibrosis, we investigated the effects of hypertension and excess aldosterone due to aldosterone-producing adenomas (APAs) on the heart., Methods and Results: In 52 hypertensive individuals, we performed Doppler echocardiography for estimation of left ventricular (LV) wall thickness and dimensions, transmitral LV filling flow velocity indexes, and 24-hour ambulatory blood pressure monitoring. Consecutive patients with APAs (n = 26) and essential hypertension (EH, n = 26) were individually matched for age, sex, race, body mass index, casual blood pressure, and known duration of hypertension. The matched groups were similar for demography, casual and 24-hour blood pressure values and variability, and duration of hypertension but differed for serum potassium, plasma renin activity, and aldosterone levels (all P < .001). A thicker interventricular septum (P = .015) and posterior wall (P = .009) and a higher LV mass index (118 +/- 5 versus 100 +/- 4 g/m2, P = .009) were observed in APA compared with EH patients. Both septum and posterior wall thicknesses had a significant direct relationship with age, plasma aldosterone, and mean blood pressure. The integral of the early diastolic filling wave (Ei) (P = .011) and the ratio Ei/Ai (A wave integral) (P = .038) were lower and the atrial contribution to LV filling was higher (52 +/- 2% versus 46 +/- 2%, P = .038) in APA than in EH patients. The ratio Ei/Ai was significantly (P = .008) inversely related only to age and plasma aldosterone., Conclusions: In APA patients, the excess aldosterone is associated with both increased LV wall thickness and mass and decreased early diastolic LV filling indexes compared with demographically similar EH with superimposable blood pressure values, profile, and variability.

Hypertension and atherosclerosis are the two leading causes of cardiovascular morbidity and mortality. They often coexist in individual patients and one may cause and/or aggravate the other. In recent years a widespread application of molecular biology techniques has led to identification of genetic polymorphisms associated with hypertension and cardiovascular events. Several clinical studies have begun to unravel the pathophysiologic diversity of hypertensive patients as well as the heterogeneity of their cardiovascular disease. A number of peptide growth factors, which through paracrine and autocrine mechanisms may be involved in vascular remodeling and atherogenesis in hypertensive subjects, have been identified. The endothelium has been found to play a pivotal role in the control of vascular tone. Given its strategical location, it is likely to work as a sensor and transducer, which mediates the atherogenic effect of blood pressure, hemodynamic, and humoral changes. We discuss herein the role of the genetic and endothelial factors in the light of recent knowledge gained on the biology of peptide growth factors.