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POINT-COUNTERPOINT COMMENTS
Medical College of Wisconsin and
Zablocki Veterans Affairs Medical Center
The following letters are in response to Point:Counterpoint: "Release of an endothelium-derived vasoconstrictor and RhoA/Rho kinase-mediated calcium sensitization of smooth muscle cell contraction are/are not the main effectors for full and sustained hypoxic pulmonary vasoconstriction" that appears in this issue.
To the Editor: Obviously, I'm prejudiced, but evidence for the PASMC as the main effector for HPV seems compelling, not only because of our work (1) kindly cited by Rochefort and Michelakis (5), but also because of work not mentioned. Murray et al. (2) showed that fetal calf PASMCs grown on a flexible membrane could generate tension when exposed to hypoxia. Olson et al.'s (3), provocative study in the dorsal aorta of the most primitive vertebrate, the cyclostome, suggests that hypoxic vasoconstriction is phylogenetically ancient and inherent to vascular smooth muscle. This vessel exhibited repeatable and sustained hypoxic contractions without preconditioning and without an endothelium or contributions from other agonist pathways. Olson et al. (3) postulate that evolution has resulted in the almost exclusive association of hypoxic vasoconstriction to respiratory organs in the higher vertebrates and that "it has been embellished with secondary regulatory mechanisms" such as those from the endothelium. Tweaking, embellishing, and reinforcing seem to be common themes in nature and maybe Robertson's argument for an endothelium derived contracting factor is based on the glitz and not the grit of HPV. Finally, Robertson (4) uses the trauma of isolation to argue against the PASMC as the effector of HPV. If the cells were traumatized, how could they contract to hypoxia? Isolation and the resultant loss of an endothelial contractile factor did not confer this ability upon them. In isolated arteries, however, HPV is often lost after any manipulation that disrupts the vessel's functional integrity (think mechanical and/or chemical endothelium removal).
REFERENCES
University of Strathclyde
Glasgow, United Kingdom
To the Editor: Cultured or dispersed pulmonary vascular smooth muscle cells can constrict when subjected to hypoxia and a very large body of evidence implicates oxygen-sensitive K+ (and perhaps other) ion channels. However the question that is ignored by the proponents of smooth muscle ion channels is whether cells in culture are behaving normally. Thus the challenge for Rochefort and Michelakis (2) is to devise an experiment that will demonstrate oxygen-sensitive ion channels in an intact pulmonary artery. Numerous studies of pulmonary artery rings in vitro (provided they have experimental verification that the endothelium was destroyed) have shown that the hypoxic contraction is dependent on the presence of the endothelium (6). However a sine qua non in these experiments is the presence of "resting" arterial tone, a dynamic balance of preconstruction and endogenous (mainly endothelial) vasodilation. This is demonstrated by the dependence of hypoxic contraction on the level of preconstriction and further contraction caused by inhibition of NO synthase (6). Under these conditions, a contraction is caused by withdrawal of a tonic vasodilator influence. Indeed inhibition of NO synthase prevents hypoxic constriction of isolated artery rings (3, 4). Thus the challenge for Robertson (5) is to devise an experiment that will demonstrate that pulmonary rings generate a vasoconstrictor (that can be distinguished from loss of a vasodilator) to match the time course of the contraction. It has already been shown that hypoxia inhibits NO formation by the endothelium (1). NO regulates arterial tone through simultaneous modulation of several pathways, one of which is to inhibit calcium sensitization. Thus the evidence for an involvement of Rho or Rho kinase in HPV is compatible with NO withdrawal.
REFERENCES
Indiana University
School of Medicine
Indianapolis, Indiana
To the Editor: We very much enjoyed the authors’ elegant papers and we agree with the conclusion that Rho kinase plays an important role in the sustained phase of hypoxic pulmonary vasoconstriction (4). In regard to the endothelium-derived vasoconstrictor, selective endothelin receptor A blockade has been shown to attenuate acute and chronic HPV in both intact rats and isolated rat lungs (5), suggesting that the endothelin system plays a significant role in HPV. However, as Drs. Rochefort and Michelakis (1) point out, it seems unlikely that a process as complex as HPV should have a single dominant culprit mediator. It appears plausible that sustained HPV, similar to other processes such as the regulation of systemic vascular resistance, is mediated by multiple mechanisms. For example, sustained HPV is also mediated by protein kinase C and p38 MAP kinase (2, 6). Voltage-gated K+ channels have been proposed to be a central mediator of HPV since their regional selectivity to the pulmonary vasculature matches that of HPV. However, while both restoration of K+ channel function and Rho kinase inhibition decrease pulmonary artery pressures in chronic hypoxic vasoconstriction, neither approach has been shown to completely normalize PA pressures (3). We have learned from several diseases that therapeutic manipulation of multiple pathways is more beneficial than treating one single pathophysiological mechanism alone. In addition, many investigators are also performing the needed examinations of pharmacogenetics and sex differences in these models. To attenuate the deleterious effects of sustained HPV (like chronic pulmonary hypertension and cor pulmonale), a multimodal approach targeting Rho kinase and endothelial factors as well as redox balance and voltage-gated K+ channels will hopefully drive us close to perfect control.
REFERENCES
University of California
San Diego, California
To the Editor: I appreciate the frank exchange of views and comprehensive discussion between both authors and enjoy reading the discussions on the issue (1, 3). The major function of the lung is gas exchange, and hypoxic pulmonary vasoconstriction (HPV) is undoubtedly a critical physiological mechanism for maximizing oxygenation of the venous blood. An important physiological mechanism like HPV must have multiple pathways to assure its effectiveness and consistency. To ensure the reliability of HPV, multiple cell types, different mediators, various membrane proteins, and diverse intracellular signaling cascades should be involved (and accurately coordinated) in stimulating smooth muscle to contract (and to relax). A rise in cytosolic Ca2+ ([Ca2+]cyt), along with an increase in Ca2+ sensitization, has been implicated as a major mechanism involved in smooth muscle contraction or vasoconstriction. How many proteins, molecules, and signaling pathways are involved in regulating [Ca2+]cyt, binding Ca2+/calmodulin to contractile proteins, or movement of actomyosin? The answer is, a lot. Therefore, why do we fantasize for a single mechanism, or the mechanism, by which alveolar hypoxia causes pulmonary vasoconstriction? Can't we trust the outcome of evolution that may have precisely "designed" a heterogeneous network to guarantee HPV? Isn't it possible that alveolar hypoxia, the initial trigger for HPV, is just a "playboy" who uses whatever he can get (simply, easily, quickly, and inexpensively) to achieve the goal? As an old saying goes, all roads lead to Rome. It is time for all investigators to sit together in a meeting held at a high-altitude or hypoxic environment and try to draw a map of the network (2, 4–6).
REFERENCES
1Cellular and Integrative Physiology
Indiana University School of Medicine
2National Science Foundation
To the Editor: Whether hypoxia causes vasoconstriction or vasodilation is dependent on vascular smooth muscle type and not on presence of the endothelium (5, 6). Mammalian pulmonary arterial and venous muscles both contract to hypoxia (5, 6), a phenomenon defined as hypoxic pulmonary vasoconstriction (HPV). Yet arteries and veins have dissimilar endothelia. Hypoxic vasoconstriction is not limited to mammalian pulmonary vasculature but is manifested in a variety of vessels from a variety of species (1, 4). While Robertson argues that HPV is often biphasic (2), biphasic responses are actually reported in relatively few vessel types from relatively few species, perhaps only in rat pulmonary artery. Rat pulmonary veins respond to hypoxia with a monophasic contraction (5). Robertson refers only to literature that supports the idea that the second sustained phase of rat HPV is endothelium dependent (2). However, others report that the early short-lived phase of hypoxic contraction is the only endothelium-dependent component (6). Importantly, Rochefort and Michelakis (3) point out that neither the biphasic nature nor the pretone or pretreatment requirement (i.e., preconditioning or precontracting) of the rat pulmonary arterial response to hypoxia is a universal feature of HPV. Indeed, pig, hagfish, lamprey, and the California blackworm can be added to the list of species in which hypoxic vasoconstriction occurs without preconditioning (1, 4). Perhaps the conflicting results of studies in which the endothelium has been removed might be explained by trauma to the underlying smooth muscle that occurs in the hands of some investigators but not in the hands of others during the endothelial denudation process.
REFERENCES
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