The Neuronal Control of Hypoxic Ventilation

HYPOXIA AND CONSEQUENCES

The Neuronal Control of Hypoxic Ventilation

Erythropoietin and Sexual Dimorphism

Max Gassmann,a Martha Tissot van Patot,b and Jorge Soliza,c

aInstitute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for IntegrativeHuman Physiology (ZIHP), University of Zurich, Zurich, Switzerland

bDepartment of Anesthesiology, University of Colorado Denver Health Sciences Center,Denver, Colorado, USA

cCentre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Faculte SaintJerome, France

Using mice, we demonstrated that when oxygen supply is lowered, erythropoietin (Epo),the main regulator of red blood cell production, modulates the ventilatory response byinteracting with central (brainstem) and peripheral (carotid bodies) respiratory centers.We showed that enhanced Epo levels in the brainstem increased the hypoxic ventila-tory response, and that intracerebroventricular injection of an Epo antagonist (solubleEpo receptor) abolished the ventilatory acclimatization to hypoxia. More recently, wehave found that the impact of Epo on ventilation occurs in a sex-dependent manner.Keeping in mind that women are less susceptible to several respiratory sicknesses andsyndromes than men, we suggest that Epo plays a key role in sexually-dimorphic hy-poxic ventilation. Accordingly, we foresee that Epo has a potential therapeutic use astreatment for hypoxia-associated ventilatory diseases.

Key words: carotid body; brainstem; sexual dimorphism; erythropoietin (Epo); hypoxia;ventilation

Introduction

Many recent studies, including our own con-tributions, show that the kidney is not the onlyorgan producing erythropoietin (Epo) and thatEpo has tissue-protective functions, especiallyin the brain and retina.1 Proof-of-concept tri-als revealed that stroke patients receiving in-travenous rhEpo had better recovery than theplacebo group.2 Apart from its neuroprotec-tive function in pathological events such as is-chemia, we recently discovered that Epo has aunique physiological role in hypoxic conditions:It modulates the ventilatory response when oxy-

Address for correspondence: Max Gassmann, DVM, Institute ofVeterinary Physiology, Vetsuisse Faculty and Zurich Center for Inte-grative Human Physiology (ZIHP), Winterthurerstrasse 260, CH-8057Zurich, Switzerland. Voice: +41-44-635-8816; fax: [email protected]

gen supply is lowered, a situation occurringin patients suffering from chronic obstructivepulmonary diseases (COPD) or in people ex-posed to high altitude. Based on this obser-vation, we recently proposed that Epo linksthe hematological and ventilatory response tohypoxia. While it takes days for high plasmaEpo to increase erythropoietic activity, cir-culating Epo immediately interacts with thecarotid body, and cerebrally produced Epo in-stantly influences central respiratory centers.Both events regulate ventilation in hypoxicconditions.

Most of our experiments were performed us-ing three male mouse models: wild type (WT)with and without recombinant Epo or antago-nist, Epo overexpressing transgenic mice withhigh Epo levels in brain only (Tg21),3 or Epooverexpressing transgenic mice with high Epolevels in brain and plasma (Tg6). The latter

Hypoxia and Consequences: Ann. N.Y. Acad. Sci. 1177: 151–161 (2009).doi: 10.1111/j.1749-6632.2009.05028.x c© 2009 New York Academy of Sciences.

151

152 Annals of the New York Academy of Sciences

leads to excessive erythrocytosis and hematocritlevels of up to 90%.4 Epo had a dramatic effecton the pattern of ventilation, increasing res-piratory frequency (fR, respirations/min) anddecreasing tidal volume (VT, ml/100 g), result-ing in either maintenance (moderate hypoxia,10% O2) or elevating (severe hypoxia, 6% O2)overall ventilation (VE, ml/min/100 g). Mostprobably, cerebral Epo achieved this result viaactivation of Epo receptor (EpoR) located inthe pre-Botzinger complex, the nucleus trac-tus solitarii and catecholaminergic cell groupslocalized in brainstem respiratory areas.5

Accordingly, we observed that cerebral Epooverexpressed in Tg21 mice enhanced the hy-poxia ventilatory response (HVR) and acclima-tization to acute and chronic hypoxia, whilethe intracerebroventricular injection of solubleEpoR,6 a negative regulator of Epo’s binding tothe Epo receptor, completely abolished ventila-tory acclimatization to hypoxia. Furthermore,following bilateral transection of carotid si-nus nerves (chemodenervation), Tg21 mice re-sponded to severe hypoxia with sustained ven-tilation, while chemodenervated WT animalsshowed life-threatening apneas and gaspingpatterns.6

These results imply that cerebral Epo is akey factor in the stimulation of ventilation un-der conditions of reduced oxygenation. Our re-sults also demonstrated that plasma Epo mod-ulates ventilatory patterns tidal volume (VT)and respiratory rate (fR) via carotid bodies (themain peripheral sensors promoting appropriateresponses to oxygen deficiency). Moreover, re-combinant human Epo (rhEpo) intravenouslyinjected in male WT mice was able to alterthe ventilatory pattern during severe hypoxia.5

In support of this, we found, by immunohis-tochemistry, that carotid glomus cells expressEpoR. Interestingly, when performing similarexperiments in transgenic Tg6 male mice (highbrain and systemic Epo), we found that despitehematocrit values up to 90%, normoxic and hy-poxic VE were not different from WT controlsiblings. Nevertheless, during hypoxia the Tg6males showed dramatic changes in the ventila-

tory pattern with greater respiratory frequencybut decreased tidal volume.7 Taken together,these results imply that endogenous Epo reg-ulation in the central and peripheral nervoussystems plays a crucial role in regulating oxygenhomeostasis, thereby ultimately contributing tothe same goal as kidney synthesized Epo; in-creasing overall oxygen delivery capacity. Note,however, that these data were obtained frommale animals only.

Sexual Dimorphism in theVentilatory Response to Hypoxia

Sex hormones include androgens (e.g.,testosterone, androstenedione), estrogens (e.g.,estradiol, estrone, and estriol), and proges-terone. Despite being primarily synthesized inthe adrenal glands, gonads, and placenta, thesecirculating hormones target the brain in an im-portant way as they easily cross the blood brainbarrier. Notably, steroid hormones are also syn-thesized in the brain and are called neuros-teroids.8 These hormonal factors are classicallyinvolved in endocrine regulation and partici-pate in the modulation of neural respiratorycontrol, either indirectly (i.e., through changesin metabolic rate) or directly, via interactionwith one or multiple cellular components ofthe respiratory control network. In adult mam-mals ovarian steroids represent potent respira-tory stimulants acting on both peripheral andcentral nervous systems to enhance basal ven-tilation and hypoxic responsiveness. Moreover,several reports have demonstrated sex-relateddifferences in the physiological responses to hy-poxia, revealing that women and other femalemammals have a better capacity to adapt tohypoxia.8,9 Gender plays a major role in therespiratory response to acute, intermittent, orchronic hypoxia. Indeed, women and femaleanimals are less susceptible to a number ofhypoxia-associated syndromes both in their in-fancy and during adulthood.

In adult mammals the experimental dataclearly show that endogenous ovarian steroids

Gassmann et al.: Epo Mediates Sex-Dependent Ventilation 153

Figure 1. Determination of basal ventilation, hypoxic ventilatory response (HVR), bodytemperature, and metabolism in WT, Tg21, and Tg6 female mice. (A, B, C) Normoxicbasal ventilation. Hypoxia was achieved in two steps of 15-min gradual reduction of FIO2(represented by ); first step from 21% to 10% O2 and second step from 10% to 6% O2. (D,E, F) VE, fR, and VT were evaluated in WT control and in transgenic (Tg21 and Tg6) miceover 20 min at 10% and at 6% O2. (G) Determination of body temperature, (H) VO2, and(I) VCO2 in WT, Tg21, and Tg6 mice. §P < 0.05 Tg21 vs. WT, at same fraction of inspiredO2; ∗P < 0.05 Tg6 vs. WT, at same fraction of inspired O2. Animals per group = 9–12.

act directly on peripheral chemoreceptors, in-creasing carotid sinus nerve activity, restingminute ventilation and hypoxic chemorespon-siveness.10,11 In rats the stimulatory effects ofovarian steroids on resting minute ventilationare mediated by a mechanism involving re-duction of dopamine synthesis and signalingon D2 dopamine receptors in the carotid bod-

ies.8 In addition to the effects on peripheralchemoreceptors, ovarian steroids (progesteroneand estradiol) stimulate resting ventilation andthe central translation of carotid body inputsduring hypoxic stimulation. Ovarian steroidsact on central areas, including the nucleustractus solitarii, medulla oblongata, and hy-pothalamic nuclei.11,12 The central effect of


progesterone on phrenic nerve activity is ab-solutely dependent on estrogen-induced de novo

synthesis of progesterone receptors in hypotha-lamic nuclei.13 Whereas the central effect ofprogesterone is not mimicked by any othersteroid tested (i.e., cortisol, testosterone, orestradiol),14 testosterone was shown to indi-rectly stimulate breathing in male cats via el-evated basal metabolic rate and directly in-creased carotid sinus nerve response to hypoxia.However, testosterone failed to exert a specificeffect on the central translation of peripheralchemoreceptor inputs during hypoxic expo-sure.15 On the other hand, in our own studies,we found no evidence of altered hypoxic ven-tilatory response or catecholamine metabolismin the carotid bodies following gonadectomyin male rats living under chronic hypoxic con-ditions, while ovariectomy drastically reducedhypoxic ventilatory response and enhanced cat-echolamine synthesis and dopamine utilizationin the carotid body of female rats.8

Epo Modulates Hypoxic Ventilationin a Sex-Dependent Manner

As described in the introduction, by usingmale mice we have provided evidence that Epoin transgenic mice (Tg6 and Tg21) modulatesthe hypoxic ventilatory response by interact-ing with peripheral and central respiratory con-trol centers. However, as mentioned above, hy-poxic ventilation is a sex-dependent process.8,16

Therefore, we evaluated HVR in WT and Epotransgenic female mice. Interestingly, comparedto transgenic male and WT female controls,Tg6 female mice had significant elevations inventilation VE and ventilatory patterns fR andVT during normoxia and hypoxia (Fig. 1). In-terestingly, the normoxic VE rise was due togreater VT while the hypoxic VE rise was dueto fR (Figs. 1B, C, E, and F). Higher VE in Tg6females compared to their male siblings sug-gests that female ventilation is more sensitiveto Epo stimulation. In line with these results,sex differences in ventilatory patterns were also

revealed when normoxic and hypoxic ventila-tion were evaluated in female mice with in-creased concentrations of Epo in the brain only(Tg21). This animal model allowed us to test theimpact of cerebral Epo in the observed Epo-mediated sex-dependent model, omitting theinfluence of the overexpressed plasma Epo andexcessive erythrocytosis that are intrinsic in Tg6mice.

Compared to WT controls, only severe hy-poxia (6% O2) elicited higher VE response inTg21 females (Fig. 1D). A similar effect wasnoted between male Tg21 and WT mice.5 Sim-ilar to findings in male Tg21 mice, female tg21mice had significantly different ventilatory pat-

terns compared to their WT littermates—lowerfR/higher VT during normoxia and higher fRand VT during hypoxia (Figs. 1B, C, E, andF).Taken together, these data strongly supportthe notion that EPO has a sex-dependent im-pact in the control of ventilation. Furthermore,keeping in mind that Epo and estradiol havefunctional interaction in several organs, includ-ing kidney17 and placenta,18 it is tempting tohypothesize that Epo and sexual steroids havea combined function in the organs controllinghypoxic ventilation. It is important to ascertainwhether the Epo ventilatory dimorphism effectoccurs at central (brainstem) and/or peripheral(carotid bodies) respiratory centers. This sub-ject is the topic of the following two sections.

Epo Impact in the Brainstem:Sex-Dimorphism and Mechanisms

Apart from activation of neuroprotectivemolecular pathways, Epo has been recog-nized as a potent factor able to modulaterelease of catecholamines from cells with neu-ronal characteristics.19,20 Knowing that cat-echolamines in the brainstem are importantfactors in the regulation of ventilation in hy-poxic conditions,21,22 we used HPLC to eval-uate the noradrenaline content and the tyro-sine hydroxylase activity in Tg6, Tg21, andWT mice. Compared to WT animals, Tg21


Figure 2. In vivo tyrosine hydroxylase (TH) activity and norepinephrine (NE) levels inbrainstem catecholaminergic cell groups. TH activity is expressed as picomoles of DOPAformed in 20 min following blockade of DOPA decarboxylase. §P < 0.05 Tg21 vs. WT;∗P < 0.05 Tg6 vs. WT. Animals per group = 8–12.


male mice showed altered catecholaminer-gic content in brainstem, higher levels inpons but lower levels in medulla. These dataare in agreement with other reports showingthat increased hypoxic ventilation—by aug-mentation of the respiratory frequency—is as-sociated with higher catecholamine level inpontial A5 cell group23,24 and lower cate-cholamine level in the medullary A1C1 andA2C2 cell groups.25 Thus, these results suggestthat cerebral Epo overexpression modulates thecatecholamine synthesis in brainstem. Whenexposed to hypoxia, this alteration affects theventilatory response by increasing the respira-tory frequency.5,7

Altered catecholaminergic metabolism wasalso observed when tyrosine hydroxylase ac-tivity and norepinephrine (NE) content weremeasured in female WT and transgenic mice(Fig. 2). However, the pattern of activityand content were distinct between malesand females. When compared to corres-ponding WT controls, both male and femaleTg21 showed higher NE content in A5 cells, butNE content was lower in A2C2 cells in malesand A1C1 cells in females. The evaluation ofnormoxic and hypoxic ventilation in Tg6 fe-male animals, with high Epo levels in brainand plasma (Tg6), also showed extensive dif-ferences. Compared to corresponding WT fe-males, Tg6 animals showed that catecholamin-ergic content was greater in A6 and A5 pontialcells, but less in A2C2 and A1C1 medullar cells.In addition, male Tg6 mice evidenced greatercatecholaminergic content in A5 cells, butno alterations in the other cell groups.7 Theseresults imply that cerebral Epo regulates theHVR in a sex-dependent manner. Keepingin mind that ovarian steroids (progesteroneand estradiol) also impact catecholaminergicmetabolism in brain tissue,26,27 one is temptedto suggest that the observed catecholaminer-gic dimorphism in transgenic mice results fromthe interaction between Epo and neurosteroids.These results support our hypothesis that cere-bral Epo mediates a sex-dependent modulationof hypoxic ventilation.

Epo Impact in Carotid Bodies: SexualDimorphism and Mechanisms

We recently provided convincing evidencethat plasma Epo influences hypoxic ventilationof male mice by interacting with carotid bodycells.5,7 In lieu of the facts that EpoR is highlyexpressed in neuronal cells and carotid bodiesoriginate from the embryonic neuroectodermallayer,28 we were not surprised to find that EpoRis expressed in the chemosensitive glomus cellsof the carotid body.5 In parallel to these find-ings, several studies on cats and rats revealedthat carotid bodies are among the major sitesfor sex differentiation of ventilatory control inhypoxia.9,10 In line with these reports, in 2002we showed that ovarian steroids stimulate ven-tilation by lowering the peripheral dopamin-ergic inhibitory drive.8 Accordingly, knowingthat both Epo and sex steroids are primaryregulators of peripheral chemoreceptors, wetested whether they have functional interaction(Fig. 3). To this end, we evaluated the transientventilatory decline in response to a brief periodof hyperoxia (Dejours test) in our male and fe-male WT and transgenic mouse lines. We foundthat the hyperoxia-induced ventilatory declinewas higher in WT females compared to WTmales. This change in WT animals was due tofR decline rather than changes in VT. Inter-estingly, sexual dimorphism was not evident inTg21 mice, in which the decline in VE, fR, andVT were similar in males and females (Fig. 3A).In contrast, Tg6 mice had a greater venti-latory decline in females compared to malesthat was due to marked reduction of fR andVT (Fig. 3A). Differing responses to hypoxiawere also evidenced when comparing Dejourstest result within females only. The hyperoxia-induced ventilatory decline was more dramaticin both transgenic female lines compared towhat was found in the female WT mice.

In a second step, we measured the im-pact of domperidone in the hypoxic ventilatoryresponse of our three mouse models. Dom-peridone is a highly specific peripheral D2-dopaminergic receptor-antagonist that induces


Figure 3. (A) Peripheral chemosensitivity to oxygen evaluated by the Dejours test. Venti-lation (VE), tidal volume (VT), and respiratory rate (fR) declined upon transition from 21% to100% O2 (Dejours test). The experiment was performed in urethane-anesthetized WT, Tg21,and Tg6 mice. Data are mean ± SD for n = 7–9 animals per group. ∗P < 0.001 for transgenicvs. WT, same gender. �P < 0.001 for females vs. males, same mouse line. (B) Ventilatoryresponse of female mice in normoxia and acute hypoxia upon i.p. injection of domperidone.Normoxic ventilation was evaluated after 1–2 h after injection of domperidone. Hypoxia wasachieved with a gradual reduction of FIO2; from 21% to 10% O2 (over 15 min) and from10% to 6% O2 (over 15 min). Ventilation was evaluated during 20 min at 10% and at 6%O2. Control animals were injected with equal volume of 0.9% NaCl. ∗P < 0.001 for femalesvs. males per group n = 6–8.


Figure 4. Hypoxic ventilatory response (HVR) in male and female mice and humans.(A) HVR upon acute i.v. injection of rhEpo in WT male and female mice. HVR at 10% O2and 6% O2 were evaluated by a step reduction of oxygen in WT males and females afteracute i.v. injection of rhEpo (2,000 U kg−1). Control animals were injected with equal volumeof 0.9% NaCl. ∗P < 0.006. Animals per group = 7–8. The bars represent the average ofventilation during 20-min exposure time. (B) Ventilatory parameters evaluated in male andfemale human volunteers upon i.v. injection of Epo. Data recording was performed undernormoxic conditions for 5 min. Then, the oxygen concentration was further reduced to 10%over the next 2 min and recordings were performed for 15 min. This protocol was repeatedusing the same volunteers, with subjects receiving acute injection of 5,000 U of rhEpo or saline5 min before being acutely exposed to 10% O2. During the entire experimental time subjectswere in supine position. ∗P < 0.05. Male subjects per group = 13. Female subjects pergroup = 7. The bars corresponding to 10% O2 represent the average of ventilation during15 min exposure time.

carotid sinus nerve discharge, thus increas-ing ventilation.7,8 Injection of domperidone in-creased normoxic and hypoxic ventilation infemale WT, but only normoxic ventilation inTg21 females (Fig. 3B). However, in Tg6 fe-males, ventilation was not altered during nor-moxia or hypoxia after domperidone injec-tion. The observed increase of ventilation innormoxic and hypoxic WT females, and innormoxic Tg21 females was due to the stim-ulation of VT rather than fR. Domperidoneapplication did not alter the ventilatory patternin Tg6 females. As with other ventilatory re-

sponses, sex differences were observed betweendomperidone injected males and females: Nor-moxic ventilation of WT and transgenic fe-males was higher than ventilation in the corre-sponding males (Fig. 3B). However, in hypoxicconditions (10% and 6% O2) only WT and tg6females showed significantly higher ventilationthan males, while no difference was observedin Tg21 animals.

Because these experiments show that plasmaEpo contributes to sex-dependent ventilation,we tested Epo’s impact on male and femaleWT animals. Assuming that no or low amounts


of Epo will cross the blood−brain barrier,29,30

we measured the HVR in male and femaleWT mice following intravenous injection of2,000 U/kg of rhEpo. This experiment allowedus to study the sex-dependent impact of Epoon carotid bodies without the influence of cere-brally produced Epo. While no differences wereobserved in male mice during hypoxia, applica-tion of Epo to female animals caused a tremen-dous increase of hypoxic ventilation31 (Fig. 4A).Taken together, these results provide convinc-ing evidence that plasma Epo modulates thecarotid body’s response to hypoxia in a sex-dependent manner.

Finally, to test whether the situation pic-tured by our data in mice parallels the situ-ation in humans, we evaluated the HVR involunteers exposed to 10% O2 for 15 minupon intravenous injection of rhEpo. Indeedwe observed that increased plasma Epo con-centration altered HVR in all human subjects.However, while HVR was decreased in mendue to a significant decrease of fR rather thanVT, HVR was augmented in women due toa significant increase of VT rather than fR31

(Fig. 4B). Because we do not expect significantamounts of Epo to cross the blood−brain bar-rier in this short period of time, our results sug-gest that elevated Epo plasma levels influenceperipheral chemosensitivity in both mice andhumans.

Clinical Implications and FutureResearch

About 140 million people live at altitudesabove 2,500 m and thus are permanently ex-posed to hypoxia.32 Plasticity of the chemore-flex pathway in the central nervous systemand peripheral chemoreceptors allows humansand mammals to adapt to hypoxic conditionsand therefore to live permanently at altitudeshigher than 4,000 m, such as populations na-tive to the Tibetan (4,200 m) and the Andean(3,900 m) plateaus.33 Several molecular path-ways are involved in chemoreflex regulation

during hypoxic exposure, and molecular mech-anisms governing the integration and interplayof these molecules in shaping the final respira-tory output remain poorly understood. In thisregard, our novel findings are relevant to under-standing both the adaptive molecular processesas well as the respiratory disorders occurringat high altitude. In addition, these processesmust be also understood at sea level whereCOPD, a group of lung diseases that includechronic bronchitis, emphysema, and small air-ways disease, is a major cause of death. Theincidence of COPD is increasing34 and is ex-pected to be the third leading cause of deathworldwide by 2020, exceeded only by cardiacdisease and stroke.35,36 Furthermore, COPDkills more people every year in Europe andthe US than bowel, breast, or prostate can-cer.36 Moreover, appropriate breathing con-trol and optimal oxygen supply during earlylife is a determinant factor for the normaldevelopment of the respiratory control net-work,37,38 as well as for several cognitivetasks.39,40 Apnea of prematurity, neonatal as-phyxia, and respiratory distress syndrome inpremature infants are among the most impor-tant factors associated with impaired oxygendelivery to the brain.41,42

The clinical importance of sexual dimor-phism in ventilatory control is revealed in thefact that women are better protected than menagainst major disorders of respiratory control,as described above,8 and the fact that femalehormones play a protective role in hypoxia-associated illnesses and syndromes.43 In lieu ofthese clinical facts, our recent discovery thatEpo is a key factor controlling the hypoxicventilation and has an important role in theventilatory sexual dimorphism process suggeststhat Epo interacts with sex steroids to controlventilation as reflected by the schematic rep-resentation of our data on male and femalemice (Fig. 5). Our work also reveals that Epoplays a crucial role in regulating the systemicoxygen homeostasis by regulating both cen-tral (brainstem) and peripheral (carotid bodies)respiratory centers and clearly demonstrates


Figure 5. Schematic comparison of acute hy-poxic ventilatory response (HVR) between mousestrains and sexes. Acute HVR was evaluated in maleand female mice of our three mouse strains: WT mice,Epo overexpressing transgenic mice with high Epolevels in brain only (Tg21: 4-fold over WT), andEpo overexpressing transgenic mice (Tg6) with highEpo levels in brain (12-fold over WT) and plasma(26-fold over WT). Tg21, but not Tg6, males showedhigher HVR than the corresponding WT males. In fe-males, Tg6 mice showed the highest HVR, the HVRobserved in Tg21 females being higher than the onein WT. Overall, the hypoxic ventilatory sexual differ-ence observed in WT animals was significantly dimin-ished in the Tg21 strain but drastically augmented inthe Tg6 strain.

that brainstem respiratory nuclei and carotidbody glomus cells in females have higher sensi-tivities to Epo. Thus, keeping in mind that Epois used therapeutically to protect against infarctand stroke,44,45 our data open new avenues ofexploration for the therapeutic use of Epo incardiorespiratory disorders including cardio-vascular diseases, and COPD. Further, thesenew findings will provide key data concerningthe poorly understood physiological role of Epoin the control of ventilation and its therapeuticuse during hypoxic exposure throughout life.

Acknowledgments

We would like to thank V. Joseph and P.Urcell for fruitful discussions. This work wassupported by the Swiss National Science Foun-dation and the Roche Foundation for AnemicResearch (RoFAR).

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Grimm, C. et al. 2002. HIF-1-induced erythropoietinin the hypoxic retina protects against light-inducedretinal degeneration. Nat. Med. 8: 718–724.

2. Ehrenreich, H. et al. 2002. Erythropoietin therapy foracute stroke is both safe and beneficial. Mol. Med. 8:495–505.

3. Wiessner, C. et al. 2001. Increased cerebral infarctvolumes in polyglobulic mice overexpressing erythro-poietin. J. Cereb. Blood Flow Metab. 21: 857–864.

4. Ruschitzka, F.T. et al. 2000. Nitric oxide prevents car-diovascular disease and determines survival in poly-globulic mice overexpressing erythropoietin. Proc.

Natl. Acad. Sci. USA 97: 11609–11613.5. Soliz, J. et al. 2005. Erythropoietin regulates hypoxic

ventilation in mice by interacting with brainstem andcarotid bodies. J. Physiol. 568: 559–571.

6. Soliz, J., M. Gassmann & V. Joseph. 2007. Downregu-lation of soluble erythropoietin receptor in the mousebrain is required for the ventilatory acclimatizationto hypoxia. J. Physiol. 583.1: 329–336.

7. Soliz, J. et al. 2007. Acute and chronic exposure to hy-poxia alters ventilatory pattern but not minute ven-tilation of mice overexpressing erythropoietin. Am.

J. Physiol. Regul. Integr. Comp. Physiol. 293: R1702–R1710.

8. Joseph, V. et al. 2002. Dopaminergic metabolism incarotid bodies and high-altitude acclimatization infemale rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.

282: R765–R773.9. Pequignot, J.M. et al. 1997. Influence of gender and

endogenous sex steroids on catecholaminergic struc-tures involved in physiological adaptation to hypoxia.Pflugers Arch. 433: 580–586.

10. Tatsumi, K. et al. 1997. Role of endogenous femalehormones in hypoxic chemosensitivity. J. Appl. Physiol.

83: 1706–1710.11. Hannhart, B., C.K. Pickett & L.G. Moore. 1990.

Effects of estrogen and progesterone on carotid bodyneural output responsiveness to hypoxia. J. Appl. Phys-

iol. 68: 1909–1916.12. Bayliss, D.A. & D.E. Millhorn. 1992. Central neural

mechanisms of progesterone action: application tothe respiratory system. J. Appl. Physiol. 73: 393–404.

13. Bayliss, D.A., J.A. Cidlowski & D.E. Millhorn. 1990.The stimulation of respiration by progesterone inovariectomized cat is mediated by an estrogen-dependent hypothalamic mechanism requiring geneexpression. Endocrinol. 126: 519–527.


14. Bayliss, D.A. et al. 1987. Progesterone stimulates res-piration through a central nervous system steroidreceptor-mediated mechanism in cat. Proc. Natl. Acad.

Sci. USA 84: 7788–7792.15. Tatsumi, K. et al. 1994. Effects of testosterone on

hypoxic ventilatory and carotid body neural respon-siveness. Am. J. Respir. Crit. Care Med. 149: 1248–1253.

16. Joseph, V. et al. 2000. Gender differentiation of thechemoreflex during growth at high altitude: func-tional and neurochemical studies. Am. J. Physiol. Regul.

Integr. Comp. Physiol. 278: R806–R816.17. Mukundan, H., T.C. Resta & N.L. Kanagy. 2002.

17Beta-estradiol decreases hypoxic induction of ery-thropoietin gene expression. Am. J. Physiol. Regul. In-

tegr. Comp. Physiol. 283: R496–R504.18. Moritz, K.M., G.B. Lim & E.M. Wintour. 1997. De-

velopmental regulation of erythropoietin and ery-thropoiesis. Am. J. Physiol. 273: R1829–R1844.

19. Tanaka, J. et al. 2001. Involvement of tetrahydro-biopterin in trophic effect of erythropoietin on PC12cells. Biochem. Biophys. Res. Commun. 289: 358–362.

20. Yamamoto, M. et al. 2000. Stimulating effect of ery-thropoietin on the release of dopamine and acetyl-choline from the rat brain slice. Neurosci. Lett. 292:131–133.

21. Hilaire, G. et al. 2004. Modulation of the respiratoryrhythm generator by the pontine noradrenergic A5and A6 groups in rodents. Respir. Physiol. Neurobiol.

143: 187–197.22. Soulage, C. et al. 2004. Chemosensory inputs and

neural remodeling in carotid body and brainstemcatecholaminergic cells. Adv. Exp. Med. Biol. 551: 53–58.

23. Dick, T.E. & S.K. Coles. 2000. Ventrolateral ponsmediates short-term depression of respiratory fre-quency after brief hypoxia. Respir. Physiol. 121: 87–100.

24. Hilaire, G. & B. Duron. 1999. Maturation of themammalian respiratory system. Physiol. Rev. 79: 325–360.

25. Champagnat, J. et al. 1979. Catecholaminergic de-pressant effects on bulbar respiratory mechanisms.Brain Res. 160: 57–68.

26. Cameron, N.M., G.K. Ha & M.S. Erskine. 2004.Fos expression after mating in noradrenergic cells ofthe A1 and A2 areas of the medulla is altered byadrenalectomy. J. Neuroendocrinol. 16: 750–757.

27. Zhang, D. et al. 2008. Estrogen regulates responses ofdopamine neurons in the ventral tegmental area tococaine. Psychopharmacol. (Berl.) 199: 625–635.

28. Kondo, H., T. Iwanaga & T. Nakajima. 1982.Immunocytochemical study on the localization ofneuron-specific enolase and S-100 protein in thecarotid body of rats. Cell Tissue Res. 227: 291–295.

29. Brines, M.L. et al. 2000. Erythropoietin crosses theblood-brain barrier to protect against experimentalbrain injury. Proc. Natl. Acad. Sci. USA 97: 10526–10531.

30. Marti, H.H. 2004. Erythropoietin and the hypoxicbrain. J. Exp. Biol. 207: 3233–3242.

31. Soliz, J. et al. 2009. Sex-dependent regulation of hy-poxic ventilation in mouse and man is mediated byerythropoietin. Am. J. Physiol. Regul. Integr. Comp. Phys-

iol. 296(6): R1837–R1846.32. Moore, L.G., S. Niermeyer & S. Zamudio. 1998.

Human adaptation to high altitude: regional and life-cycle perspectives. Am. J. Phys Anthropol. Suppl 27:25–64.

33. Beall, C.M. 2007. Two routes to functional adapta-tion: Tibetan and Andean high-altitude natives. Proc.

Natl. Acad. Sci. USA 104(Suppl 1): 8655–8660.34. Murray, C.J. & A.D. Lopez. 1997. Alternative projec-

tions of mortality and disability by cause 1990–2020:Global Burden of Disease Study. Lancet 349: 1498–1504.

35. Mannino, D.M. & A.S. Buist. 2007. Global burdenof COPD: risk factors, prevalence, and future trends.Lancet 370: 765–773.

36. Lopez, A.D. et al. 2006. Chronic obstructive pul-monary disease: current burden and future projec-tions. Eur. Respir. J. 27: 397–412.

37. Gaultier, C. 2000. Development of the control ofbreathing: implications for sleep-related breathingdisorders in infants. Sleep 23(Suppl 4): S136–S139.

38. Ling, L. et al. 1996. Attenuation of the hypoxic venti-latory response in adult rats following one month ofperinatal hyperoxia. J. Physiol. 495(Pt 2): 561–571.

39. Antier, D. et al. 1998. Effects of neonatal focalcerebral hypoxia-ischemia on sleep-waking pattern,ECoG power spectra and locomotor activity in theadult rat. Brain Res. 807: 29–37.

40. Gozal, D. 1998. Sleep-disordered breathing andschool performance in children. Pediatrics 102: 616–620.

41. Lipton, P. 1999. Ischemic cell death in brain neurons.Physiol. Rev. 79: 1431–1568.

42. Tuor, U.I., M.R. Del Bigio & P.D. Chumas. 1996.Brain damage due to cerebral hypoxia/ischemia inthe neonate: pathology and pharmacological modi-fication. Cerebrovasc. Brain Metab. Rev. 8: 159–193.

43. Basnyat, B. & D.R. Murdoch. 2003. High-altitudeillness. Lancet 361: 1967–1974.

44. Bahlmann, F.H. 2008. Use of erythropoietin for car-diovascular protection. Cardiovasc. Drugs Ther. 22:253–255.

45. Liu, X.B. et al. 2008. Therapeutic strategy of erythro-poietin in neurological disorders. CNS Neurol. Disord.

Drug Targets 7: 227–234.

The Neuronal Control of Hypoxic Ventilation

Documents

Transcript of The Neuronal Control of Hypoxic Ventilation