Relationship Between Vascular Damage Degrees and Endothelial Progenitor Cells in Patients with Erectile Dysfunction: Effect of Vardenafil Administration and PDE5 Expression in the Bone Marrow

Abstract

Objectives

To evaluate the levels of circulating progenitor cells (PCs) and the effect of a single dose of vardenafil 20 mg on the number of these cells in men with erectile dysfunction (ED) and various degree of vascular injury at the carotid artery level.

Methods

Sixty-eight patients with ED and various degree of carotid damage, and 25 controls were enrolled. Patients were divided into three groups according to their intima media thickness (IMT) status (normal, mild increase, or plaque). All subjects received vardenafil 20 mg, and evaluation of the number of circulating PCs was performed at baseline and 4 h after vardenafil administration. An RNA expression analysis of phosphodiesterase type 5 (PDE5) on bone marrow was also performed.

Results

We found a significant reduction of circulating PCs in ED patients with respect to controls and a reduction in PC counts in patients with mild IMT increase or plaque, but not in those with normal IMT. Four hours after vardenafil administration we observed an increase in the number of PCs in all patients and controls. Reverse transcriptase-polymerase chain reaction analysis showed that human bone marrow expresses PDE5 messenger RNA.

Conclusions

Patients with ED and a low number of circulating PCs may be considered at increased risk for an endothelial dysfunction. An impaired response to vardenafil stimulus may be proposed as a surrogate marker of a patient’s endothelial regenerative ability.

Introduction

There is growing evidence for a pathophysiologic and epidemiologic association between erectile dysfunction (ED) and common cardiovascular risk factors, such as hypertension, smoking, diabetes, and hyperlipidemia [1], [2]. Such an association has been confirmed also by the Massachusetts Male Aging Study and the Cologne Male Survey study [3], [4]. The link between ED and cardiovascular diseases (CVDs) seems to be represented by an endothelial dysfunction. In fact, vascular endothelium is not only a simple barrier, but a true organ that synthesizes and releases substances, playing in a paracrine and endocrine manner on vascular tone and platelet aggregation [5]. ED is the first sign of CVD and may present well before CVD in men with free medical history [6].

In humans, extended endothelial cell (EC) damage by cardiovascular risk factors can result in EC apoptosis with loss of integrity of the endothelium. The increased vascular permeability of the endothelium is followed by vascular smooth muscle cell proliferation, facilitated migration of monocytes with lipid deposition, and activation of proinflammatory cytokines, resulting in neointima formation and, finally, in the irreversible manifestation of an atherosclerotic lesion [7], [8]. The enhancement of re-endothelialization can prevent this detrimental neointima formation [9], [10].

In the last few years, it has been demonstrated that an injured endothelial monolayer is restored by circulating bone marrow-derived EPCs [11], [12]. These cells migrating into peripheral circulation and differentiating into mature ECs are able to provide a circulating pool of cells that may contribute not only to endothelial repair, but also to neovascularization. The mobilization of stem cells from the bone marrow is a complex mechanism not yet clarified, but nitric oxide (NO) availability at this level seems to be essential for the functional activity of haematopoietic stem cells and PCs [13]. There is good evidence that statins and angiotensin-converting enzyme (ACE) inhibitors mediate in part their pleiotrophic and vasculoprotective action via EPCs [14], [15]. In addition physical activity and estrogens were shown to influence EPC numbers and function [16], [17].

Patients with ED, with or without overt cardiovascular risk factors, show reduced EPC numbers [18]. Interestingly, phosphodiesterase type 5 (PDE5) inhibitors, vardenafil (acutely and in healthy subjects) and tadalafil (chronically and in ED patients), were shown to increase the circulating number of PCs, suggesting an intriguing role of these drugs in the mobilization and/or production of EPCs [19], [20].

In the present study we evaluated the relationship between degrees of vascular damage and the amount of EPCs in patients with ED, and the effect of a single dose of vardenafil (at baseline and 4 hours afterward). The main goal of our study was to evaluate if a single dose of vardenafil, in patients stratified for carotid artery damage, could be used as a mirror of an impaired bone marrow ability to mobilize and/or produce EPCs.