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Am J Physiol Heart Circ Physiol 286: H2052-H2056, 2004. First published February 12, 2004; doi:10.1152/ajpheart.00978.2003
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Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion

Erik N. T. P. Bakker, Oana Sorop, Jos A. E. Spaan, and Ed VanBavel

Department of Medical Physics and Cardiovascular Research Institute, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands

Submitted 21 October 2003 ; accepted in final form 9 February 2004


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The hypothesis was tested that pressure and pressure pulsation modulate vascular remodeling. Arterioles (~200 µm lumen diameter) were dissected from rat cremaster muscle and studied in organoid culture. In the first series, arterioles were kept at a stable pressure level of either 50 or 100 mmHg for 3 days. Both groups showed a progressive increase in myogenic tone during the experiment. Arterioles kept at 50 mmHg showed larger endothelium-dependent dilation, compared with vessels kept at 100 mmHg on day 3. Remodeling, as indicated by the reduction in maximally dilated diameter at 100 mmHg, was larger in arterioles kept at 50 mmHg compared with 100 mmHg: 34 ± 4.5 versus 10 ± 4.8 µm (P < 0.05). In the second series, arterioles were subjected to a stable pressure of 60 mmHg or oscillating pressure of 60 ± 10 mmHg (1.5 Hz) for 4 days. Pressure pulsation induced partial dilation and was associated with less remodeling: 34 ± 4.0 versus 19 ± 4.5 µm (P < 0.01) for stable pressure versus oscillating pressure. Vasomotion was frequently observed in all groups, and inward remodeling was larger in vessels with vasomotion: 30 ± 2.5 µm compared with vessels that did not exhibit vasomotion: 8.0 ± 5.0 µm (P < 0.01). In conclusion, these results indicate that remodeling is not enhanced by high pressure. Pressure pulsation causes partial dilation and reduces inward remodeling. The appearance of vasomotion is associated with enhanced inward remodeling.

myogenic regulation; vascular adaptation; hypertension

MYOGENIC REGULATION plays an important role in the dynamic control of tissue perfusion, especially at the level of small arteries and arterioles, i.e., the resistance arteries. The myogenic response can be demonstrated on isolated arterioles where the diameter returns to the initial value or below within a few minutes on a stepwise increase in pressure (13, 14), thereby reducing wall stress. Whereas myogenic regulation plays a role in the moment-to-moment regulation of perfusion, chronic changes in pressure are associated with structural adaptation. Thus an increase in the arterial wall thickness-to-lumen diameter ratio is found in hypertension. In the resistance arteries, this increase is largely attributed to a rearrangement of cells and extracellular matrix around a smaller lumen, a process referred to as remodeling (8). It has been suggested that this inward remodeling normalizes arterial wall stress (10).

Whereas the relationship between pressure and arterial tone has been demonstrated in acute experiments, the causal relationship between pressure and remodeling is less clear. We have recently described inward remodeling of resistance arteries on chronic activation with contractile factors. The remodeling was shown to be dependent on vasoconstriction, as remodeling was fully prevented by vasodilatory compounds (1). In addition, remodeling was not observed at low pressure (2 mmHg) where vessels passively collapsed to a diameter similar as during vasoconstriction (1). Thus these data indicate that remodeling depends on an active reduction in diameter, and that pressure plays a role herein. Building up to these findings, we hypothesized that strong myogenic constriction, as induced by high pressure, may enhance inward remodeling. Thus remodeling may be the structural consequence of a chronically enhanced myogenic tone, linking the acute and structural reduction in diameter of small arteries associated with high pressure. To test this hypothesis, we used an in vitro approach that allows independent manipulation of pressure. Because arteries not only experience blood pressure, but also oscillations herein, we also subjected arterioles to stable and oscillating pressure protocols for several days. The data show that pressure and pressure pulsation modulate vasoconstriction, vascular responses, and remodeling. However, inward remodeling is not enhanced by high pressure. Interestingly, rhythmic vasomotion was found to be associated with inward remodeling.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
RESULTS
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Procedures were done under the approval of the local committee for animal experiments. Male Wistar rats (250–300 g) were sedated by inhalation of CO2 and then decapitated. The cremaster muscle was dissected under sterile conditions and placed in a cold buffer composed of (in mol/l) 145 NaCl, 4.7 KCl, 1.2 NaH2PO4, 1.2 MgSO4, 2 CaCl2, 3 3-(N-morpholino)propanesulfonic acid, 5 glucose, and 2 pyruvate, pH 7.4. The technique for organoid culture of arterioles was described in detail previously (3). Briefly, segments of 3- to 4-mm length of the first-order arteriole were dissected and mounted in an organ culture system under sterile conditions. Arterial lumen diameter was recorded continuously. In all experiments, the perfusate, but not the superfusate, was supplemented with 10% heat-inactivated FCS. The preparation was kept at 34°C, the in vivo temperature of the cremaster muscle. In the first series of experiments, arteries were kept in DMEM containing penicillin 100 IU/ml, and streptomycin 0.1 mg/ml. The solution was equilibrated with 19% O2-76% N2-5% CO2. The vessels were first allowed to develop myogenic tone at 75 mmHg and then pressure was changed stepwise to either 50 or 100 mmHg and maintained at this level for 3 days. These pressure levels induce moderate and strong myogenic tone in this arteriole (6), respectively, whereas its in vivo pressure is ~60 mmHg (2). At the end of the experimental period, pressure in both groups was set to 75 mmHg for 1 h and responses to substance P (10–7 mol/l) and serotonin (3·10–7 mol/l) were tested. Substance P was used to induce endothelium-dependent dilatory responses, and serotonin (3 x 10–7 mol/l) was used to induce contractile responses. Responses to these agonists were tested at the end of the experiment only, to minimize the exposure to vasoactive substances at the start of culture. Passive pressure-diameter relations were recorded on day 0 in a fully dilated state, induced by 10–4 mol/l papaverin and on day 3 after full dilation with Ca2+-free PSS containing 10–4 mol/l papaverin. Vessels were exposed to Ca2+-free PSS on day 3 only to prevent possible harmful effects of this condition during culture. In the second series, Leibovitz culture medium was used, which does not require CO2 to maintain pH. The medium was supplemented with 100 IU/ml penicillin, 0.1 mg/ml streptomycin, and 5 mg/l Ciproxin. The arteries were studied pairwise and subjected to either 60 mmHg or to an oscillating pressure, imposed as a sine wave of 60 ± 10 mmHg (1.5 Hz) for 4 days. The amplitude of the oscillations was based on previous in vivo measurements (2). The choice for the frequency of pressure oscillations was based on technical concerns and previous work (12). This previous work demonstrated that pulsation-induced dilation was constant in the range of 0.5 to 2.5 Hz.

Calculations and statistics. Data are expressed as means ± SE, where n is the number of arterial segments studied. ANOVA was used to determine the significance of differences between multiple mean data. A paired or unpaired t-test was used for all other comparisons. Differences were considered significant at P < 0.05.

Chemicals. DMEM, Leibovitz medium, penicillin, and streptomycin were obtained from GIBCO Invitrogen (Breda, The Netherlands). Ciproxin was obtained from Bayer (Mijdrecht, The Netherlands). FCS was obtained from BioWhitaker (Verviers, Belgium). Substance P and serotonin were obtained from Sigma (St. Louis, MO). Salts were obtained from Merck (Darmstadt, Germany).


   RESULTS
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Effect of pressure on tone and remodeling. After being mounted, arteries developed myogenic tone at 75 mmHg, from a passive diameter of 195 ± 5 µm to 134 ± 6 µm (n = 11). The arteries were then kept at either 50 mmHg (n = 6) or 100 mmHg (n = 5) for 3 days. During this period, segments kept at 50 mmHg initially dilated partially after the reduction in pressure, as a result of myogenic regulation. A gradual decrease in diameter was then observed during days 2 and 3 (Fig. 1). Arteries kept at 100 mmHg also showed a gradual decrease in active diameter during the culture period. The active diameter of these vessels was significantly smaller at day 1 of the culture period compared with vessels kept at 50 mmHg. Myogenic tone, the level of constriction normalized to the respective passive diameters at days 0 and 3, increased from 22 ± 6% to 50 ± 6% (P < 0.05) for vessels kept at 50 mmHg. For vessels kept at 100 mmHg, myogenic tone increased similarly, from 33 ± 3% to 59 ± 7% (P < 0.05). Between groups, the difference in myogenic tone did not reach statistical significance (P = 0.07).



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  		Fig. 1. Arterial lumen diameter during organoid culture. Initially, vessels developed myogenic tone at 75 mmHg. The vessels were then kept at either 50 mmHg (n = 6) or 100 mmHg (n = 5) for 3 days. The diameter of arteries kept at 100 mmHg was significantly smaller during the culture period (P < 0.01). For the individual time points, the diameter of arteries kept at 100 mmHg was smaller at day 1 (P < 0.05).

 
At the end of the culture period vasomotor responses were tested at 75 mmHg. Whereas the diameter before the addition of substance P in both groups was similar: 68 ± 7 versus 62 ± 18 µm for 50 versus 100 mmHg, endothelium-dependent dilation was smaller in segments previously kept at 100 mmHg (P < 0.05). Contractile responses to serotonin were not significantly different between the two groups but showed a tendency to reduction after culture at 100 mmHg (Fig. 2).



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  		Fig. 2. Responses to substance P (10–7 mol/l) and serotonin (3 x 10–7 mol/l) after culture at 50 mmHg (left; n = 6) or 100 mmHg (right; n = 5). Responses were tested at 75 mmHg. Dilatory responses to substance P were significantly smaller after culture at 100 mmHg (*P < 0.05).

 
For arteries kept at 50 mmHg, the passive pressure-diameter relationship showed a marked reduction in diameter after 3 days. Whereas the reduction in diameter was small at low pressure, a pronounced decrease in passive diameter was observed at higher pressure levels (Fig. 3A). In contrast, the arteries kept at 100 mmHg showed only a modest decrease in passive diameter, reaching statistical significance at operational pressures of 25 and 50 mmHg only (Fig. 3B).



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  		Fig. 3. Pressure-diameter relationship of arteries under fully relaxed conditions. A: pressure-diameter relationship for arteries kept at 50 mmHg for 3 days (n = 6). A significant reduction in diameter was found at each pressure level on day 3 compared with day 0. B: pressure-diameter relationship for arteries kept at 100 mmHg for 3 days (n = 5). The diameter was significantly decreased at two pressure levels. *P < 0.05; **P < 0.01.

 
Effect of pressure pulsation on tone and remodeling. Arteries kept at a steady pressure level of 60 mmHg showed a gradual decrease in the active diameter during the culture period. The arteries subjected to oscillatory pressure only showed a tendency to a decrease in diameter during the culture period, which did not reach statistical significance (P = 0.06). The active diameter of arteries subjected to oscillatory pressure was larger compared with arteries kept at steady pressure during the culture period. The difference in diameter was statistically significant at most time points (Fig. 4).



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  		Fig. 4. Arterial diameter during organoid culture. Arteries were kept at a stable pressure of 60 mmHg (n = 6) or pulsatile pressure of 60 ± 10 mmHg (n = 6) for 4 days. The active diameter of arteries kept at a pulsatile pressure was significantly larger compared with arteries kept at a stable pressure level. Post hoc analysis revealed a significantly larger diameter at the indicated time points. *P < 0.05; **P < 0.01.

 
Remodeling, as revealed by the reduction in maximal diameter at full dilation, was observed in both groups (Fig. 5, A and B). However, the reduction in diameter was smaller in arteries subjected to oscillatory pressure (P < 0.05). For instance, at 100 mmHg, the diameter was reduced by 17 ± 2.5% versus 10 ± 2.1% (P < 0.01) for steady versus oscillatory pressure.



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  		Fig. 5. Pressure-diameter relationship of arteries under fully relaxed conditions. A: pressure-diameter relationship for arteries kept at a stable pressure of 60 mmHg for 4 days (n = 6). A significant reduction in diameter was found at each pressure level on day 4 compared with day 0. B: pressure-diameter relationship for arteries kept at a pulsatile pressure of 60 ± 10 mmHg for 4 days (n = 6). With the exception of the lowest pressure level, the diameter was significantly decreased on day 4 compared with day 0. *P < 0.05; **P < 0.01.

 
Vasomotion and remodeling. Vasomotion appeared in all arterioles kept at 50 mmHg (Fig. 6), a group that also showed strong remodeling. In vessels from all other groups vasomotion was observed frequently, with variable duration. Inward remodeling was found to be dependent on the appearance of vasomotion during the culture period. Vessels with vasomotion (n = 18) showed considerably more remodeling compared with vessels that did not develop vasomotion: 30 ± 2.5 vs. 8.0 ± 5.0 µm (P < 0.01) as indicated by ANOVA (Fig. 7).



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  		Fig. 6. Arterial diameter on day 2 during culture at 50 mmHg (A) and at 100 mmHg (B). Vasomotion appeared in all arteries kept at 50 mmHg and in some arteries kept at 100 mmHg.

 


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  		Fig. 7. Relationship between the appearance of vasomotion during organoid culture and inward remodeling. Inward remodeling is shown as the decrease in maximally dilated diameter at 100 mmHg. ANOVA indicated a significant (P < 0.01) effect of vasomotion on remodeling.

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Three main findings emerge from the present study. First, inward remodeling of resistance arteries is not enhanced by high pressure. Second, pulsatile pressure causes partial dilation and reduces inward remodeling. Third, inward remodeling depends on the appearance of vasomotion.

Pressurized resistance arteries show myogenic regulation, a pressure-dependent modulation of tone. Because myogenic regulation is considered to be important in the local regulation of tissue perfusion, the myogenic response has been the subject of much in vitro research on isolated arteries (for review, see Ref. 11). The present study extends to most former studies because the effect of pressure on diameter is followed for several days. The results show that arteries, kept at both pressure levels, developed a gradual increase in constriction in time, which is partially related to a concomitant decrease in the passive diameter. Because the increase in myogenic tone is similar for both groups, it seems unlikely that it is related to a change in the sensitivity of myogenic regulation. However, we cannot exclude the possibility that maintaining arterioles at a certain level of pressure for several days alters myogenic regulation.

After full dilation, arteries kept in culture at both intermediate and high pressure showed a reduction in lumen diameter. Comparison of arteries kept at 50 mmHg to those kept at 100 mmHg revealed a more pronounced reduction in the passive diameter in arteries kept at 50 mmHg. Therefore, these data clearly demonstrate that remodeling is not enhanced by high pressure.

The difference in pressure during culture affected vascular function with respect to endothelium-dependent dilation. Whereas responses were tested at the end of the experiment under identical conditions, the arteries previously kept at 100 mmHg showed reduced responses compared with those kept at 50 mmHg. These findings may relate to data that have been reported for gracilis arterioles, where flow- and endothelium-dependent responses are reduced after a 30-min exposure to high pressure (7). This impairment could be reversed by free radical scavengers (7). Thus these data suggest that high pressure induces the release of oxygen radicals, which persists for some time after pressure is returned to a more physiological level.

Pressure pulsation. We recently found that pulse pressure changes markedly along single rat cremaster resistance arteries (2). Thus along this arteriole both mean and pulse pressure decrease, whereas the diameter surprisingly increases. While we suggested that the increase in diameter resulted from the interaction of mean pressure with shear stress-related vessel widening (2), it was unclear whether also a contribution of pulse pressure to vascular caliber exists. In hypertension, the causal relationship between pulse pressure and remodeling of small arteries is also unclear. In hypertensive rats, increased pulse pressure was found to correlate with inward remodeling of the resistance arteries (4). In contrast, in a model of isolated systolic hypertension, increased pulse pressure was found to result in outward remodeling of resistance arteries (5). Moreover, in an acute study on isolated small coronary arteries, we previously observed vasodilation on pressure pulsations, which may involve increased sensitivity to vasodilatory stimuli (12). Thus, increased pulse pressure, in the absence of a change in mean blood pressure, could attenuate inward remodeling through a vasodilatory effect. The data of the present study support this hypothesis because pressure pulsation was found to reduce constriction and remodeling.

Vasomotion. A surprising finding in the present study is that the appearance of vasomotion is associated with enhanced inward remodeling. The physiological role of vasomotion is unknown at present, and whether the observed association with remodeling reflects a causal relationship is not clear. The reduction in diameter under fully relaxed conditions very likely results from changes in the extracellular matrix. Possibly, the dynamic interaction of smooth muscle cells with the extracellular matrix during vasomotion promotes the rearrangement or enhances the synthesis of extracellular matrix components responsible for remodeling. It is also possible that rhythmic elevations in smooth muscle cell cytosolic calcium regulate a signaling process relevant for rearrangement of the extracellular matrix, as vasomotion relates to synchronized Ca2+ waves (9). We did not measure cytosolic calcium in the present study and therefore can only speculate on its involvement in remodeling. However, we (14) previously found in rat mesenteric arteries that pressure-induced myogenic tone is associated with increased calcium sensitivity of the contractile apparatus rather than a large increase in cytosolic calcium concentration. Thus the lack of a clear relation between vasoconstriction and remodeling as described previously (1) may reside in the lack of a sufficient rise in cytosolic calcium when high pressure is used to induce constriction. In any case, these observations warrant a future study on the role of cytosolic calcium dynamics in remodeling.

In conclusion, the present study shows that high pressure does not promote inward remodeling of resistance arteries in organoid culture. Thus no evidence was found for the hypothesis that high pressure could contribute directly or indirectly to inward remodeling, through enhanced myogenic constriction or inhibition of endothelium-dependent dilatory responses. Pulsatile pressure reduces remodeling, associated with a vasodilatory effect. Whereas the present study was performed on intact, healthy arteries, these data favor the hypothesis that high blood pressure and increased pulse pressure may be a consequence, rather than cause of inward remodeling and vessel stiffening. Smooth muscle activation by growth factors and contractile factors such as endothelin-1 (1, 3), and in particular, the oscillatory processes underlying vasomotion, may trigger inward remodeling of resistance arteries.


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This research has been supported by The Netherlands Heart Foundation Grant NHS 2001.D038 (to E. N. T. P. Bakker) and NHS 98.180 to (to E. VanBavel).


   FOOTNOTES
 

Address for reprint requests and other correspondence: E. N. T. P. Bakker, Dept. of Medical Physics, Academic Medical Center, PO Box 22700, 1100 DE Amsterdam, The Netherlands (E-mail: n.t.bakker{at}amc.uva.nl).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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  1. Bakker EN, van der Meulen ET, van den Berg BM, Everts V, Spaan JA, and VanBavel E. Inward remodeling follows chronic vasoconstriction in isolated resistance arteries. J Vasc Res 39: 12–20, 2002.[CrossRef][ISI][Medline]
  2. Bakker EN, Versluis JP, Sipkema P, VanTeeffelen JW, Rolf TM, Spaan JA, and VanBavel E. Differential structural adaptation to haemodynamics along single rat cremaster arterioles. J Physiol 548: 549–555, 2003.[Abstract/Free Full Text]
  3. Bakker EN, van der Meulen ET, Spaan JA, and VanBavel E. Organoid culture of cannulated rat resistance arteries: effect of serum factors on vasoactivity and remodeling. Am J Physiol Heart Circ Physiol 278: H1233–H1240, 2000.[Abstract/Free Full Text]
  4. Christensen KL. Reducing pulse pressure in hypertension may normalize small artery structure. Hypertension 18: 722–727, 1991.[Abstract/Free Full Text]
  5. Dao HH, Essalihi R, Graillon JF, Lariviere R, de Champlain J, and Moreau P. Pharmacological prevention and regression of arterial remodeling in a rat model of isolated systolic hypertension. J Hypertens 20: 1597–1606, 2002.[CrossRef][ISI][Medline]
  6. Falcone JC, Davis MJ, and Meininger GA. Endothelial independence of myogenic response in isolated skeletal muscle arterioles. Am J Physiol Heart Circ Physiol 260: H130–H135, 1991.[Abstract/Free Full Text]
  7. Huang A, Sun D, Kaley G, and Koller A. Superoxide released to high intra-arteriolar pressure reduces nitric oxide-mediated shear stress- and agonist-induced dilations. Circ Res 83: 960–965, 1998.[Abstract/Free Full Text]
  8. Mulvany MJ. Vascular remodelling of resistance vessels: can we define this? Cardiovasc Res 41: 9–13, 1999.[Free Full Text]
  9. Peng H, Matchkov V, Ivarsen A, Aalkjaer C, and Nilsson H. Hypothesis for the initiation of vasomotion. Circ Res 88: 810–815, 2001.[Abstract/Free Full Text]
  10. Prewitt RL, Rice DC, and Dobrian AD. Adaptation of resistance arteries to increases in pressure. Microcirculation 9: 295–304, 2003.
  11. Schubert R and Mulvany MJ. The myogenic response: established facts and attractive hypotheses. Clin Sci (Lond) 96: 313–326, 1999.[Medline]
  12. Sorop O, Spaan JA, and VanBavel E. Pulsation-induced dilation of subendocardial and subepicardial arterioles: effect on vasodilator sensitivity. Am J Physiol Heart Circ Physiol 282: H311–H319, 2002.[Abstract/Free Full Text]
  13. VanBavel E, Giezeman MJ, Mooij T, and Spaan JA. Influence of pressure alterations on tone and vasomotion of isolated mesenteric small arteries of the rat. J Physiol 436: 371–383, 1991.[Abstract/Free Full Text]
  14. VanBavel E, Wesselman JP, and Spaan JA. Myogenic activation and calcium sensitivity of cannulated rat mesenteric small arteries. Circ Res 82: 210–220, 1998.[Abstract/Free Full Text]



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