Gender differences in cardiovascular function are well known. Hormones and related receptors are critically important factors, but clinical studies are revealing potential gender differences in afferent mediated autonomic nervous system (ANS) function. Some ANS assessments of cardiovagal reflexes have proven to be sexually dimorphic. In this study we investigate hypotheses related to possible neuroanatomical, neuophysiological and biophysical differences between aortic baroreceptors (BR) in male and female rats. A gender-related bias in aortic BR fiber type, pressure encoding and neurohormonal regulation may reveal as yet unrecognized mechanisms associated with noted gender differences in integrated cardiovagal control. This proposal builds upon our previous studies quantifying the differential composition of ionic channels in myelinated and unmyelinated BR afferents and the manner in which this defines the strikingly different reflex control of heart rate and blood pressure evoked by these neuroanatomically distinct afferent pathways.
The first aim examines gender-related differences in rat aortic BR afferents. Morphometric analysis of aortic BR fibers and study of fluorescently identified aortic BR neurons (ABN) gives preliminary evidence that female rats have ~50% more myelinated BR, revealing, for the first time, a functionally distinct subtype of low threshold myelinated ABN rarely present (~2%) in age-matched males.
The second aim quantifies the neuromodulatory capacity of estradiol (E2) upon this unique subtype of BR afferents. Nerve recordings show that E2 can increase the pressure-dependent discharge of single myelinated aortic BR fibers from female rats. Physiological levels of E2 (0.1 - 1 nM) acting, at least in part, via membrane bound estrogen receptors can selectively increase the excitability of this ABN subtype in female rats. Interestingly, E2 had no effect upon unmyelinated ABN from either gender.
The third aim determines if E2 can alter K+ ion channel function in a manner consistent with the observed increased excitability. Our preliminary data show that, unlike all myelinated ABN in males and the balance of myelinated ABN from females, this unique subset expresses BKCa channels that provide ~25% of the whole cell potassium current. We further show that E2 selectively inhibits this BKCa current, offering one potential mechanism for the E2 sensitization of myelinated BR excitability in female rats. Finally, in aim four we determine if E2 can alter monosynaptic transmission of BR afferents onto 2nd-order BR neurons in the NTS. In male rats, monosynaptic transmission of myelinated afferents to the NTS does not involve BKCa channels. In stark contrast, E2 in female rats can increase monosynaptic transmission of myelinated afferent pathways with companion studies implicating a role for BKCa channels. Gender-related differences in the neural integration of BR sensory information from the afferent terminal through to 2nd-order BR neurons in the NTS could potentially lead to novel advances in the management of cardiovascular health and disease in the female population.

Public Health Relevance

Gender differences in cardiovascular function are well known and while sex hormones are important contributing factors, there is growing evidence for alternative mechanisms. This project aims to determine if there are fundamental neuroanatomical and neurophysiological differences in the baroreceptor afferent pathway between men and women. Evidence for a gender-related difference in baroreceptors could potentially lead to novel advances in the effective management of cardiovascular health and disease in the female population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL072012-08
Application #
8208239
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Maric-Bilkan, Christine
Project Start
2002-12-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
8
Fiscal Year
2012
Total Cost
$438,638
Indirect Cost
$151,677
Name
Indiana University-Purdue University at Indianapolis
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Santa Cruz Chavez, Grace C; Li, Bai-Yan; Glazebrook, Patricia A et al. (2014) An afferent explanation for sexual dimorphism in the aortic baroreflex of rat. Am J Physiol Heart Circ Physiol 307:H910-21
Li, Bai-Yan; Glazebrook, Patricia; Kunze, Diana L et al. (2011) KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents. Am J Physiol Cell Physiol 300:C1393-403
Maruyama, Mitsunori; Li, Bai-Yan; Chen, Hanying et al. (2011) FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice. Circ Res 108:1042-52
Zhou, Yu-Hong; Sun, Li-Hua; Liu, Zhen-Hong et al. (2010) Functional impact of the hyperpolarization-activated current on the excitability of myelinated A-type vagal afferent neurons in the rat. Clin Exp Pharmacol Physiol 37:852-61
Qiao, Guo-Fen; Li, Bai-Yan; Lu, Yan-Jie et al. (2009) 17Beta-estradiol restores excitability of a sexually dimorphic subset of myelinated vagal afferents in ovariectomized rats. Am J Physiol Cell Physiol 297:C654-64
Qiao, Guo-Fen; Li, Bai-Yan; Zhou, Yu-Hong et al. (2009) Characterization of persistent TTX-R Na+ currents in physiological concentration of sodium in rat visceral afferents. Int J Biol Sci 5:293-7
Li, Bai-Yan; Qiao, Guo-Fen; Feng, Bin et al. (2008) Electrophysiological and neuroanatomical evidence of sexual dimorphism in aortic baroreceptor and vagal afferents in rat. Am J Physiol Regul Integr Comp Physiol 295:R1301-10
Wladyka, Cynthia L; Feng, Bin; Glazebrook, Patricia A et al. (2008) The KCNQ/M-current modulates arterial baroreceptor function at the sensory terminal in rats. J Physiol 586:795-802
Li, Bai-Yan; Feng, Bin; Tsu, Hwa Y et al. (2007) Unmyelinated visceral afferents exhibit frequency dependent action potential broadening while myelinated visceral afferents do not. Neurosci Lett 421:62-6
Li, Baiyan; Schild, John H (2007) Persistent tetrodotoxin-resistant Na+ currents are activated by prostaglandin E2 via cyclic AMP-dependent pathway in C-type nodose neurons of adult rats. Biochem Biophys Res Commun 355:1064-8

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