Influence of blood flow on arteriolar wall-to-lumen ratio in the human retinal circulation in vivo

Abstract

Objective

We hypothesized that blood flow impacts on arteriolar wall-to-lumen ratio and that vasodilatory capacity is negatively related to arteriolar wall-to-lumen ratio in the human retinal vascular bed.

Methods

The study cohort comprised 141 non-diabetic untreated male patients with (n = 52) or without (n = 89) arterial hypertension but without evidence for cardiovascular disease. Retinal capillary blood flow (RCF) before and after exposure to flicker light and to infusion of nitric oxide (NO) synthase inhibitor N-monomethyl-l-arginine (L-NMMA), and parameters of retinal arteriolar morphology, e.g. wall-to-lumen ratio, were assessed non-invasively and in vivo by scanning laser Doppler flowmetry.

Results

The study cohort was grouped according to the median RCF into two groups. Patients with RCF above the median revealed lower wall-to-lumen ratio (0.30 ± 0.1 vs 0.34 ± 0.1 (−), P adjusted = 0.023) compared to patients with RCF equal or below the median. In addition, RCF was negatively related to wall-to-lumen ratio independently of cardiovascular risk factors (ß = − 0.224, P = 0.026). In parallel, the decrease of RCF to L-NMMA infusion was greater in patients with RCF above the median compared to the counter group (− 8.95 ± 11 vs. 0.35 ± 15 (%), P adjusted < 0.001). The increase in RCF to flicker light exposure was negatively related to wall-to-lumen ratio in hypertensive but not in normotensive or all patients (r = − 0.292, P = 0.047, r = − 0.035, P = 0.746 and r = − 0.126, P = 0.144, respectively).

Conclusions

In the retinal circulation blood flow impacts on arteriolar wall-to-lumen ratio. Basal NO activity might modulate blood flow and arteriolar morphological changes. In hypertensive, but not in normotensive patients, the vasodilatory capacity is negatively related to arteriolar wall-to-lumen ratio in the human retinal vascular bed.

Introduction

Blood flow supplies the tissue of a specific vascular bed with oxygen and metabolic substrates according to the needs of the tissue. Among others, local metabolites and, in circumstances of the presence of local autoregulatory mechanisms, also myogenic responses to changes in systemic hemodynamics determine local blood flow in the tissue. Changes in blood flow go along with changes in shear stress thereby modulating the release of shear-responsive endothelial derived vasoactive metabolites, such as nitric oxide (NO). In parallel, precapillary arterioles, that act as major gate keepers of tissue perfusion, might undergo short-term and long-term, i.e. arteriolar remodeling, morphological changes. On the other hand, in patients revealing remodeled precapillary arterioles, with the consequence of reduced vasodilatory capacity (Rizzoni et al., 2003a), local blood flow might be impaired despite the increased metabolic demand of the tissue.

Remodeled small arteries and arterioles are characterized by an altered wall(media)-to-lumen ration of the vessel due to reorientated vascular wall components around a changed lumen (inner) diameter and/or hypertrophy or atrophy of vascular wall components (Intengan and Schiffrin, 2001, Izzard et al., 2005, Mulvany, 2002, Van den Akker et al., 2010). Such remodeling processes of small arteries and arterioles were found in patients with sustained elevation in blood pressure and sustained changes in blood flow and neurohumoral environment (Intengan and Schiffrin, 2001, Izzard et al., 2005, Mulvany, 2002). Of most interest, clinical studies in hypertensive patients have found that media-to-lumen ratio of small arteries and arterioles, that have been isolated through biopsy from subcutaneous tissue and mounted on a myograph for in vitro analysis, is of prognostic significance with respect to cardiovascular prognosis, with a more severe prognosis in those patients whose vessels have revealed a greater media-to-lumen ratio (De Ciuceis et al., 2007, Mathiassen et al., 2007, Rizzoni et al., 2003b).

Analysis of the retinal arterioles offers the opportunity to study the impact of several determinants of arteriolar morphology non-invasively and in vivo in humans. We have previously reported that blood pressure (Ritt et al., 2008) and basal NO activity (Ritt et al., 2011) are independent determinants of wall-to-lumen ratio of retinal arterioles. We have also found that wall-to-lumen ratio of retinal arterioles is related to subclinical organ damage in other vascular beds, as evidenced by the relation of the wall-to-lumen ratio of retinal arterioles to urinary albumin excretion (Ritt et al., 2009) and carotid intima–media thickness (Baleanu et al., 2009). Moreover, a greater wall-to-lumen ratio of retinal arterioles was found in patients with the history of a cerebrovascular event than in those without such a history. (Harazny et al., 2007). In a recent study a close relationship between wall-to-lumen ratio of retinal arterioles and media-to-lumen ratio of isolated subcutaneous small arteries and arterioles was observed (Rizzoni et al., 2011). Thus, we suggested that wall-to-lumen ratio of retinal arterioles might serve as an in vivo parameter for cardiovascular risk stratification. The evaluation of determinants that influence this parameter is therefore of great interest.

The impact of blood flow on the morphology of small arteries and arterioles have been well characterized in several animal experiments (Buus et al., 2001, De Mey et al., 2005, Pistea et al., 2005, Unthank et al., 1996). In models of altered blood flow acute changes in inner (lumen) arterial diameter preceded actual remodeling (Buus et al., 2001, Unthank et al., 1996). Moreover, blood flow was found to inhibit inward remodeling of small arteries and arterioles (Pistea et al., 2005). However, data concerning the relationship between blood flow and morphology and remodeling of resistance arteries in humans is scarce. In the current study we hypothesized that blood flow impacts on arteriolar wall-to-lumen ratio in the human retinal vascular bed. Moreover, we were interested whether vasodilatory capacity, that was found to be impaired in patients revealing arteriolar remodeling (Rizzoni et al., 2003a), reveals an inverse relationship to wall-to-lumen ratio of retinal arterioles.