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Selective microvascular dysfunction in mice lacking the gene encoding for desmin ¹

LAURENT LOUFRANI, KHALID MATROUGUI, ZHENLIN LI, BERNARD I. LÉVY, PATRICK LACOLLEY^*, DENISE PAULIN and DANIEL HENRION²

Institut National de la Santé et de la Recherche Médicale (INSERM) U 541, IFR-Circulation-Paris-Nord, Paris VII University, Paris, France;
^* INSERM EMI 0107, Paris VI University, Paris, France;
Department of Physiology, Paris VII University, AP-HP-Hôpital Lariboisière, Paris, France; and
Laboratoire de Biologie Moléculaire de la Différentiation, Paris VII University, Paris, France

²Correspondence: INSERM U 541, Hopital Lariboisiere, 41 Bd de la Chapelle, 75475 PARIS, cedex 10, France. E-mail: daniel.henrion{at}inserm.lrb.ap-hop-paris.fr

SPECIFIC AIM

The intermediate filament desmin has a key role in the integrity and contractile of skeletal and cardiac myocytes, and its absence or filament aggregation leads to cardiomyopathies. Desmin is present in the smooth muscle cells of blood vessels, and vascular disorders might occur when desmin is absent; thus, we examined the vasodilator and vasoconstrictor functions of large (aorta, carotid artery) and small (mesenteric resistance arteries) arteries from mice lacking the gene encoding for desmin.

PRINCIPAL FINDINGS

1. Global parameters and structural properties of the arteries
Neither body weight (31±4 vs. 34±3g, des-/- vs. control mice, n=12 per group) nor blood pressure was affected by the absence of desmin in mice (mean arterial pressure: 82±4 mmHg, n=12) vs. des+/+ mice (86±3 mmHg, n=14).

1. Large arteries
Desmin plays a role in skeletal and cardiac muscle cells, but its role in smooth muscle cells has not been elucidated, especially in arteries. We found no change in contractile or dilatory functions in large arteries from mice lacking desmin compared with control. This agrees with a previous finding in the portal vein which suggests that, in large arteries, contractile or dilatory functions may not involve desmin.

2. Microcirculation
Only small resistance arteries (100 µm internal diameter) were affected by the absence of desmin. Except for pressure-induced myogenic tone, other forms of contraction, whether receptor dependent (phenylephrine, serotonin, endothelin-1) or not (KCl), were decreased by the absence of desmin (Fig. 1 ). The dilatory machinery in smooth muscle cells of mesenteric resistance arteries was decreased in des-/- mice (Fig. 2 ). The difference between large and small arteries seems paradoxical, but may simply reflect the difference in the role of the two types of arteries. Previous studies have shown that the absence of desmin leads to disorganization and a weakening of myofibrils in cardiac cells. Indeed, cells more frequently stimulated might be more affected. This might be caused by the defect in mitochondrial function found in cells lacking desmin and a possible defect in cell-to-cell communication. The contractile and dilatory machineries of the smooth muscle cells in resistance arteries are continuously stimulated in order to control the arteriolar diameter and adapt local blood flow supply to organs’ needs. This is not the case for large arteries, which use their elastic structural property to dampen the energy produced by the ejection of blood by the heart at each systole—their contractile and dilatory functions being limited and not required as in resistance arteries. Another difference between large and small arteries is the number of cells containing desmin. Using real time confocal microscopy of living perfused arteries, we found that half the cells in the carotid artery were labeled. In the mesenteric resistance arteries, all the cells contained desmin in control mice (no trace in des-/- mice).

View larger version (40K): [in this window] [in a new window]   Figure 1. Effect of the inhibition of NO synthesis with L-NAME (0.1 mM) on flow-induced dilation (upper panel) in mesenteric resistance (left) and carotid (right) arteries isolated from desmin-/- and control (+/+) mice. In the lower panel, the inhibitory effect of L-NAME is represented as a percentage of inhibition of flow-induced dilation. (n=10 per group). *P < 0.01; two-factor ANOVA, + /+ vs. -/-.

View larger version (21K): [in this window] [in a new window]   Figure 2. Concentration-dependent contraction to phenylephrine in mesenteric arteries (upper panel), carotid arteries (middle panel), and the aorta (lower panel) from desmin-/- and control (+/+) mice. (n=6 to 10 per group). *P < 0.001; two-factor ANOVA, + /+ vs. -/-.

3. Myogenic tone
In resistance mesenteric arteries, contractions due to receptor or depolarization with KCl were decreased, but pressure-induced (myogenic) tone was unaffected by the absence of desmin. Indeed, we expected the mechanotransduction of pressure to be preferentially affected by the disorganization in the cytoskeletal network caused by the absence of desmin. In previous studies we had found that myogenic tone is unaffected by the absence of vimentin or dystrophin. This suggests that acute pressure transduction leading to the development of myogenic tone might involve either 1) a pathway requiring other cytoskeletal proteins or 2) only membrane-bound proteins such as integrins, enzymes (phospholipases, focal adhesion kinase, etc.), or G-proteins; this pathway would not involve cytoskeletal proteins in myogenic tone, or 3) the cytoskeletal network in its entirety might be required. This latter possibility calls for the integrity theory describing the whole cell as a sensing structure.

4. Pathways involving desmin
In support of a possible role of desmin in specific transduction pathways leading to contraction in the microcirculation, the small G-protein Rho kinase (which is involved in calcium-sensitization of the contractile apparatus in smooth muscle cells) has been shown to phosphorylate desmin and vimentin. Similarly, the decreased mitochondrial function and energy supply found in desmin-deficient cells might impair both dilatory and contractile function, requiring phosphorylation to develop. Calcium handling, potassium channel activity, some PKC activity, and phospholipase activity depend on the cytoskeletal integrity.

5. Structural properties of the arterial wall
No significant change in arterial wall thickness or passive diameter was found in either large or small arteries from mice lacking desmin. This could reflect an adaptation to the chronic lack of desmin, which would efficiently compensate for the absence of desmin in its structural role; i.e., other proteins can carry out the shape and the elasticity of the cells. On the other hand, the absence of desmin might be more difficult to compensate for in its functional role in smooth muscle cells because of the many processes in which desmin is involved (as described above).

6. Distribution of desmin in the arterial wall
The localization of desmin in the tunica media of large and small arteries is not homogeneous. As already shown, desmin is predominant in small arteries. In the present study, smooth muscle cells in resistance arteries were all labeled for desmin whereas only half of the cells had desmin in the carotid artery. This could explain at least in part why the absence of the protein mainly affected the contractility of resistance arteries without significantly affecting large arteries.

7. Pathophysiological considerations
Our study sheds light on a possible role for a vascular defect in desmin-related myopathies. Indeed, this has not yet been considered in these diseases. The absence of desmin in mice or its disassembly and accumulation in humans are associated with skeletal and cardiac myopathies. The absence of desmin in mice is linked to an increased cardiomyocyte volume and a lowered systolic function. In humans, desmin-related myopathies are almost exclusively related to an aggregation of filaments resulting from the disassembly of the protein, leading to a situation similar to its absence in mice: in both cases, its functions can no longer be accomplished. Our findings suggest that microvascular dilatory and contractile functions might be less efficient in patients with a desmin-related myopathy, leading to the poor adaptation of resistance arteries to situations in which a change in blood supply is necessary. This could exacerbate the damage due to the disassembly of desmin in other muscles such as the myocardium and skeletal muscles.

CONCLUSIONS

Our findings demonstrate that in resistance arteries, but not in large arteries, desmin is involved in smooth muscle cell dilatory and contractile functions (Fig. 3 ). The microvascular defects found in the absence of desmin might have an important role in the functional damages observed in desmin-related myopathies in humans.

View larger version (20K): [in this window] [in a new window]   Figure 3. Schematic representation of signaling pathways that could be affected by the absence of desmin in smooth muscle cells of mice resistance arteries.

FOOTNOTES

¹ To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.01-0505fje; to cite this article, use FASEB J. (November 29, 2001) 10.1096/fj.01-0505fje

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