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LETTER TO THE EDITOR
Previous studies have shown that hindlimb unweighting of rats, a model of microgravity, reduces evoked contractile tension of peripheral conduit arteries. It has been hypothesized that this diminished contractile tension is the result of alterations in the mechanical properties of these arteries (e.g., active and passive mechanics). Therefore, the purpose of this study was to determine whether the reduced contractile force of the abdominal aorta from 2-wk hindlimb-unweighted (HU) rats results from a mechanical function deficit resulting from structural vascular alterations or material property changes. Aortas were isolated from control (C) and HU rats, and vasoconstrictor responses to norepinephrine (10–9–10–4 M) and AVP (10–9-10–5 M) were tested in vitro. In a second series of tests, the active and passive Cauchy stress-stretch relations were determined by incrementally increasing the uniaxial displacement of the aortic rings. Maximal Cauchy stress in response to norepinephrine and AVP were less in aortic rings from HU rats. The active Cauchy stress-stretch response indicated that, although maximum stress was lower in aortas from HU rats (C, 8.1 ± 0.2 kPa; HU, 7.0 ± 0.4 kPa), it was achieved at a similar hoop stretch. There were also no differences in the passive Cauchy stress-stretch response or the gross vascular morphology (e.g., medial cross-sectional area: C, 0.30 ± 0.02 mm2; HU, 0.32 ± 0.01 mm2) between groups and no differences in resting or basal vascular tone at the displacement that elicits peak developed tension between groups (resting tension: C, 1.71 ± 0.06 g; HU, 1.78 ± 0.14 g). These results indicate that HU does not alter the functional mechanical properties of conduit arteries. However, the significantly lower active Cauchy stress of aortas from HU rats demonstrates a true contractile deficit in these arteries.
Vascular Adaptation to Microgravity
To the Editor: In the paper referred to above, Papadopoulos and Delp (5) have demonstrated that 2-wk hindlimb unweighting (HU) does not alter the medial cross-sectional area (CSA) and the passive Cauchy stress-stretch response of rat abdominal aortic ring and concluded that the previously reported reductions in vasoconstrictor responsiveness of aortic rings from HU rats (2, 6, 9) are due to a "true contractile deficit" in these arteries. They further cited other studies on small mesenteric (4, 7) and femoral arteries (9) as examples to support their view regarding the dissociation of "functional" from "structural" changes. In addition, I am afraid that Papadopoulos and Delp have also misunderstood the viewpoint expressed in my previous review paper (8). Referring to my review, Papadopoulos and Delp wrote in their discussion, "He [Zhang] suggests that there are graded alterations in arterial contractile function from the head to the hindlimbs related to these changes in arterial pressure and blood flow. ..." In addition, they wrote, "Zhang further proposes that these alterations are based on changes in arterial structure or, more specifically, due to changes in the medial cross-sectional area." Finally, they commented that Zhang's "suggestion" is "an oversimplification that does not fit all of the experimental data." I am mystified by this conclusion and unable to reconcile their viewpoints with the present concepts in vascular biology.
In my review paper (8), I wrote, "The findings thus reviewed substantiate in general the hypothesis that microgravity-induced redistribution of transmural pressures and flows across and within the arterial vasculature may well initiate differential adaptations of vessels in different anatomic regions." It is my understanding that vascular adaptation to microgravity is basically a process of vascular autoregulation to altered local hemodynamic condition caused by a loss of hydrostatic pressure gradient due to the removal of gravity. According to the present concepts in vascular biology, arterial tissue responds to sustained alterations in local stress, such as shear or cyclic stretch or both, first by an immediate change in myogenic tone and vasoreactivity, usually called "functional adaptation." When the stress continues to act locally, a remodeling process involving morphological changes of the blood vessels will occur, usually called "structural adaptation." Functional and structural changes are two interrelated and inseparable adaptation processes. It has been shown that the arterial vasculature is capable of remodeling its structure over a surprisingly short time frame. In space cardiovascular research, the concept of structural adaptation of vessels to microgravity was first raised by Dr. Alan Hargens in the 1980s and was later tested and verified by several groups in ground-based animal studies (for review, see Ref. 8). However, it is also important to extend the observation with primates and humans, using innovative noninvasive techniques, in future ground-based and International Space Station research to fill the gaps in our knowledge regarding the vascular adaptation to microgravity in humans.
With respect to what has been learned from the HU rat model, it is necessary to define the changes in the local prevailing hemodynamic conditions and relate them to the nature and time course of the functional and structural changes in the vasculature, particularly in the cerebral and mesenteric vessels, to ascertain whether these changes are causally related to the redistribution of transmural pressure and blood flow. During head-down tilt or microgravity exposure, the primary change in the vascular system is the redistribution of transmural pressure across the vasculature; a secondary consequence is blood volume redistribution due to the high compliance of the venous system. The transmural pressure distribution is maintained as long as the head-down tilt or microgravity exposure is continued, even though the blood volume redistribution attains a new equilibrium. Furthermore, the transmural pressure across the cerebral vasculature during the head-down tilt, or real microgravity, in humans or rats is further complicated by the simultaneous change in the distribution of pressure in cerebrospinal fluid. Further multidisciplinary studies are needed to better characterize the physiological mechanisms in vascular adaptation to microgravity. Although changes in large conduit arteries do not necessarily reflect those in small resistance arteries, they do share some common features. The work reported by Papadopoulos and Delp (5) is one of such unremitting efforts. However, I believe that certain adaptational changes in vessel structure of the abdominal aorta after 2 wk of HU perhaps could not be excluded; the abdominal aorta is a large elastic artery containing both smooth muscle cells and many elastic laminae, and its histomorphological and other structural changes may not be fully reflected in the change of medial CSA, which is a gross indicator. The medial CSA usually manifests obvious and prominent changes in medium-sized muscular conduit arteries after HU over 2 wk. Regarding the thoracic aorta, a more thorough understanding of the central hemodynamics is needed, as well as a consideration of the total stroke work of the heart over 24 h in different stages of HU, although an elevated ascending aortic pressure after 14 days of HU has been shown (7). The two examples given by Papadopoulos and Delp regarding small mesenteric (4, 7) and femoral (9) arteries are not appropriate to support their statement (5) that "a diminished unweighting-induced contractile response without corresponding changes in vascular structure" is possible. In the case of the femoral artery (9), my colleagues and I found that both the medial CSA and lumen diameter were significantly decreased after HU (Ref. 9 is an earlier paper; for review, see Ref. 8). Although Looft-Wilson and Gisolfi (4) have demonstrated that the myogenic tone of the second- and third-order small mesenteric arteries were attenuated with their vasoconstrictor responsiveness, internal and external diameters, and wall thickness remained unchanged after a 4-wk HU, there are some methodological aspects requiring further clarification. This is because dimensional measurements carried out in a perfusion myographic system (4) and perfusion fixation (7) both have inherent pitfalls and limitations (1). In most morphometric studies of the blood vessels, medial CSA is generally used as an indicator of the amount of contractile material within the vascular wall because it provides information regarding vascular growth and/or regression. One implicit assumption is that CSA is not affected by the contractile or relaxation state of the vessels (1). However, in isolated small arterial preparations, the estimated CSA is easily affected because of the change in vessel shape (e.g., length). Another difficulty is related to the issue of accurate sampling of comparable vessels (1).
The exact nature of the functional and structural changes of a blood vessel during its adaptation to simulated microgravity may depend on some of the following factors: its anatomic location (distance and sign from hydrostatic indifference level), vessel type (elastic vs. muscular, and conduit vs. resistive), time points of observation within the time frame of a simulation experiment (time course), and animal age. I greatly appreciate the studies performed by Delp and his colleagues, ranging from their pioneer work with aortic rings (2) to their work with muscular small arterioles (for review, see Ref. 8). However, the possible mechanisms accounting for the impairment of the smooth muscle contractile apparatus of abdominal aortic ring due to HU (2) still merits further study. A recent study in my laboratory (3) has suggested that different profiles of ion channel remodeling in vascular smooth muscle cells could play a role in mediating and modulating differential vascular adaptation during microgravity.
REFERENCES
As detailed in the discussion section of our paper (6), we understood Zhang to implicitly and explicitly state in his review (9) that alterations in the vasoconstrictor properties of arteries from HU rats are inextricably linked to alterations in arterial structure [see Figs. 1 and 2 of Zhang review (9)], a view we find to be in error. For example, we have experimentally demonstrated that altered contractile function is associated with the structural remodeling of arteries in some vascular beds of HU rats (e.g., Refs. 2 and 3), but functional and structural alterations do not always occur concomitantly in all arterial beds (e.g., Refs. 4 and 6). Zhang claims that we have misunderstood his viewpoint regarding the relation between altered vascular structure and function, but, if this is so, we are not alone. We note that, in a previous Letter to the Editor exchange with Zhang, Purdy and Kahwaji (7) also stated, "We believe his [Zhang's] hypothesis can be extended to cover impaired functional responses occurring in the absence of structural change." However, we doubt that we have misunderstood Zhang's viewpoint since he restates in this most recent letter that "[f]unctional and structural changes are two interrelated and inseparable adaptation processes." We believe the disparity between views expressed by Zhang and ourselves is not the result of our purported misconception of the present concepts in vascular biomedicine but rather Zhang's misunderstanding and misuse of terminology associated with arterial structure and vascular remodeling. In the vascular remodeling literature, structural remodeling specifically refers to changes in vessel diameter, wall thickness (or medial thickness), and wall cross-sectional area (or medial CSA). These structural parameters form the bases for describing how vessels remodel (e.g., eutrophic, hypertrophic, or hypotrophic remodeling), and these specific structural characteristics are clearly delineated in the review (1) that Zhang cites in his letter. Therefore, if a hypothetical artery were to demonstrate diminished vasoconstriction to norepinephrine resulting from a reduction in adrenergic receptors, with no change in vessel diameter, wall thickness, or wall CSA, this would represent a functional alteration independent of a structural modification. The literature is replete with such examples of functional vasoconstrictor and vasodilator alterations in arteries with no structural correlate, including some in the microgravity literature (4, 6). In reference to our study (6), Zhang states that structural adaptations in the abdominal aorta might occur if the period of simulated microgravity were to be extended. We do not disagree with this assertion; however, such a statement misses the point, which is that functional vasoconstrictor decrements are present in some arteries of HU rats where no structural or mechanical alterations have occurred (6).
The second issue raised by Zhang is in regard to the methodology for determining arterial structure. As summarized by Bund and Lee (1), each of the various approaches used to assess vascular structure have inherent advantages and disadvantages. For this reason, they have outlined certain criteria requisite to describing structural remodeling of arteries; i.e., remodeling should describe a situation in which 1) there is a change in the structure of a relaxed vessel, 2) measurements are made under a standard intravascular pressure, and 3) the altered structure cannot be accounted for by a change in wall stiffness (1).
In his letter, Zhang refers to three studies that have assessed vascular structure in HU rats: one from our laboratory (8), one from another group (4), and one from his laboratory (10). What we find most troublesome is that, in his letter, his review (9), and several of his previous publications, Zhang points out "inherent pitfalls and limitations" of other studies (4, 8) while failing to mention the potential shortcomings of the methods used in his laboratory (10). Although we do not relish criticism of our work, we accept it as a valuable means to the discovery of truth, provided that such criticism is equitable and accurate. Therefore, we will take this opportunity to contrast the various approaches used to determine vascular structure from our respective laboratories.
In our laboratory's studies of resistance arteries (3, 8), we assess structure in isolated, cannulated, precisely pressurized, and fully relaxed arteries and arterioles. As pointed out by Bund and Lee (1), precise measures of diameter and wall thickness through video imaging of cannulated and pressurized vessels may be limited. For this reason, we further fix the resistance arteries and determine the luminal circumference (to calculate diameter), medial thickness, and medial CSA histologically. In addition, we determine the passive pressure-diameter or stress-strain relations to assess wall stiffness. Thus we satisfy all the criteria put forth by Bund and Lee (1). In contrast, Zhang has used the perfusion fixation technique to determine vascular structure (see Ref. 10). In general, this method suffers from incomplete relaxation of arteries or unintentional activation of vessels during fixation, unknown intravascular pressures of distal arteries during fixation, and, consequently, potential variations in intraluminal pressure among experimental animals (1, 5). Furthermore, Zhang and colleagues do not state in their study (10) whether any attempt was made to induce vascular relaxation before fixation and do not make any indication that vascular stiffness was assessed. Thus it is not clear whether any of the criteria put forth by Bund and Lee (1) for determining vascular structure were satisfied in Zhang's work describing arterial remodeling in HU rats (10). In addition to these technical considerations, there exists a paucity of other critical details necessary to judge the merits of Zhang's work and place it in the context of the existing literature. The strain, sex, age, and body mass of the rats used, the degree to which the unweighting procedure altered body mass (a critical consideration with HU rat studies), and the number of animals and vessels studied are not reported. Furthermore, no absolute measures of vascular structure are provided, only percent changes (10). Because such vital experimental and methodological details are missing from a number of Zhang's original studies (cf., Ref. 9), including some of those forming the basis of his vascular structure-function hypothesis [see cited studies in Fig. 1 legend of Zhang's review (9)], we have often chosen not to cite this work in our publications rather than question and disparage Zhang's results.
In closing, we agree with Dr. Zhang that the redistribution of arterial transmural pressures and blood flow during actual or simulated weightlessness serves as a potent stimulus to induce structural and functional arterial remodeling. However, we also recognize that other nonmechanical factors can likewise influence vascular structure and/or function, including electrical and biochemical factors. Although we do not always agree with Zhang's concepts regarding cardiovascular adaptations to microgravity, we look forward to a continued and open exchange of ideas, which will ultimately lead us to a better understanding of how gravitational stress affects cardiovascular function.
REFERENCES
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