Invited Symposium: Hypertension III: Flow-Induced Vascular Remodeling


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Compensatory And Mal-Adaptive Arterial Remodeling In Rodent Models Of Altered Blood Flow.

Contact Person: Jo G R De Mey (j.demey@farmaco.unimaas.nl)


In this presentation we summarize facts and concepts concerning remodeling of resistance arteries in response to altered blood flow. We focus on the functional and pathological relevance of the process. In doing so we hope to strengthen the suggestion that resistance artery remodeling is a plausible target for (drug-) therapy of various aspects of cardiovascular diseases. Full elaboration of this reasoning is hindered by a lack of detailed knowledge concerning mechanisms of certain aspects of arterial remodeling (e.g. what is the ultrastructural basis of arterial lumen diameter and what are the molecular mechanisms that lead to a persistent change of this ultrastructure).

We state that flow-induced resistance artery remodeling contributes to chronic maintenance of hyperemia. In this view, pharmacological improvement of the process may be beneficial in ischemia resulting from atherosclerotic large artery disease and in hypertensive and diabetic complications of pregnancy. Along the same lines, impairment of flow-induced resistance artery remodeling may help reduce the perfusion and growth of solid tumors and may be beneficial in other pathological conditions characterized by hyperperfusion such as diabetic retinopathy and rheumatoid arthritis.

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At the start of this presentation we like you to agree on a limited number of definitions.

1. A resistance artery is a muscular artery with a diameter that is sufficiently small and a contractile reactivity that is sufficiently large, for the vessel to significantly influence local resistance to blood flow and its regulation. In adult mammals, most small muscular arteries and arterioles with a diameter below 500 um fall in this category.

2. Dilatation refers to an increase in vascular lumen diameter as a result of a reduction of the tone developed by the smooth muscle coat of the vessel.

3. Remodeling refers to an alteration of the structure of a blood vessel taking into account that the structural lumen diameter and wall mass can be influenced to a different extent or with different kinetics. This implies that assessment of remodeling requires measurements of the lumen and of the wall during complete inactivation of the muscle. In view of the biaxial and pressure-dependent nature of vessel geometry, it may be wise to record both variables as volumes, rather than as two-dimesional parameters, and as function of distending pressure. Consequently we, like others, prefer that arterial remodeling is further specified: e.g. outward hypertrophic remodeling refers to an increase in lumen volume that is accompanied by an increase in wall mass while inward hypothrophic remodeling refers to a reduction of lumen size accompanied by a decrease in wall mass. It will be clear that any conclusion concerning remodeling implies that the initial vascular structure prior to the experimental intervention or disease state, has been documented and that it may be assumed to remain stable or in dynamic equilibrium under control conditions.

4. Wall shear stress (WSS) depends on blood flow (Q), blood viscosity (v) and vessel lumen radius (R) according to the formula: WSS = 4.v.Q(PI.Rexp3). It is not entirely clear whether the transient changes in WSS (and Q) during the cardiac cycle or the average WSS (and Q) during some time interval should be considered as regards modulation of vessel structure.

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Flow-induced remodeling differs in resistance and elastic arteries

In recent experiments we compared arterial remodeling in response to blood flow elevation and blood flow reduction for small muscular resistance-sized arteries and large elastic conduit vessels. For the former we used the rat mesenteric arterial bed as previously described (Pourageaud and De Mey, Am J Physiol 1997 and 1998) while for the latter we used carotid arteries in mice as described by Kumar and Lindner (Arterioscler Thromb Vasc Biol 1997). The choice for mice was inspired by the reasoning that transgenic and knock-out technology may be helpful to unravel (later) the molecular mechanisms involved in vascular structural responses to hemodynamic changes. The choice was, however, also practical in nature. It turned out to be impossible to reproduce our rat mesenteric artery model in mice. They all dyed between 24 and 48 hours after surgery. Various strains of mice seem to lack the appropriate arcading collateral channels on which the rat mesenteric models depends. Our findings in mouse carotid arteries, however, display a large degree of similarity with the findings in rat carotid arteries that can be found in the literature.

In both the rat mesentery and in mouse carotids we applied surgical interventions that resulted in near abolition of blood flow in one vessel and that resulted in a doubling of mean blood flow in the parallel vessel. Structural consequences were evaluated four weeks later.

In rat mesenteric resistance arteries: (1) hypoperfusion resulted in inward hypothrophic remodeling (reduction of both lumen diameter and media mass) and (2) hyperperfusion resulted in outward hypertrophic remodeling (significant increases of both lumen diameter and media mass). We have data to support that the media mass changes involved the arterial smooth muscle: cell loss and reduced cell volume in the case of hypoperfusion, and cellular proliferation in the case of hyperperfusion. Both forms of remodeling seemed to be adaptive in nature as calculated WSS and circumferential wall stress were normalized.

In carotid arteries of Swiss and Bl6/57 mice: (1) chronic hypoperfusion resulted in a marked reduction of lumen and outer diameter and in a substantial (20%) media hypertrophy, while (2) chronic hyperperfusion did not result in significant lumen diameter or media changes. In mice carotid arteries subjected to reduced or elevated blood flow, calculated wall shear rate and circumferential wall stress were not normalized after 4 weeks.

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Why study flow-induced arterial remodeling of resistance arteries?

In our hands, as in those of many before us, small muscular resistance-sized arteries can display considerable structural changes in response to altered blood flow (or shear stress). Resistance artery remodeling in response to altered blood flow is much more pronounced than that in elastic conduit vessels. At present, we can only speculate as regards this discrepancy and consider regional differences in the pulsatility of local hemodynamic factors, and in abundance of smooth muscle cells, extracellular matrix components and in cytoskeletal components such as desmin and vimentin, as potential determinants.

According to Borst and colleagues, remodeling of the underlying media influences the extent to which a growing neointima can lead to a flow-limiting stenosis. Maybe findings in resistance arteries can lead us the way to (pharmaco-) therapeutic strategies that improve the patency of atherosclerotic arteries before and after angioplasty.

Findings in resistance arteries can be of direct relevance as well. This includes both conditions of hypoperfusion and conditions of undesirable hyperperfusion. Almost by definition, flow-induced dilatation and remodeling of resistance arteries affects resistance to blood flow.

In ischemia, resulting from large artery occlusion, the perfusion of the tissue depends on pre-existing or newly formed collateral channels exposed to a pressure gradient. The ease with which these channels can widen, and reduce their resistance, in response to the established flow will determine the survival and functionality of the post-stenotic tissue.

Conversely, the growth of solid tumors has been demonstrated to depend on their perfusion. Considerable attention is being paid in this respect to tumor angiogenesis and to the signals generated by the tumor and by its immediate environment that trigger the formation of new blood vessels. Adding new terminal vessels to a pre-existing arterial tree, however, affects blood flow only marginally. Resistance must fall through dilatation and/or remodeling of the upstream arterioles and resistance arteries.

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In rodent models, flow-induced arterial remodeling seems to be more pronounced in small muscular resistance arteries than in elastic conduit vessels. Elucidation of the mechanisms in resistance arteries may ultimately help us prevent restenosis, improve collateral circulations in ischemia and blunt tumor blood flow.

Though endothelium-dependency of flow-induced arterial remodeling has only been demonstrated for a limited number of large elastic artery models, it may be workable to focus future research on the roles played by the endothelium and by the vasoactive and growth-modulating mediators that it can release.

We thank you for your interest.

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De Mey, J.; Schiffers, P.; Ceiler, D.; Fazzi, G.; (1998). Compensatory And Mal-Adaptive Arterial Remodeling In Rodent Models Of Altered Blood Flow.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/prewitt/de_mey0657/index.html
© 1998 Author(s) Hold Copyright