Impact of Teaching Social Determinants of Health on PIF in the Health Professions.

OBJECTIVE: To address the lack of methods for assessing learning on social determinants of health, particularly from a health systems perspective. Using a conceptual framework of professional identity formation applied across 3 professions (athletic training, occupational therapy, and pharmacy), the study aimed to describe students' level of professional identity when applying knowledge of structural factors' impact on health. METHODS: This study was a deductive content analysis of students' written reflections. Identified themes explored how students explained sociopolitical influences on health as well as their assessed level of professional identity. RESULTS: Students were inclined to author narratives focused on the ways in which structural factors influence individual outcomes and aspects within the health care system. Most students were assessed to be at the initial levels of professional identity formation, but those with a comparatively higher level of professional identity expressed a commitment to professional behaviors that address social determinants of health. CONCLUSION: This analysis created a foundation for future pedagogical work in health care system-related structural learning outcomes within and between different health professions. Findings suggest that across professions, most first-year students demonstrated the ability to reconcile different perspectives and were in the early stages of aligning personal values with professional values. The use of reflection has the potential to assess professional identity formation among a range of health professional students.

Antiproteinuric therapy and Fabry nephropathy: factors associated with preserved kidney function during agalsidase-beta therapy.

BACKGROUND: Nephropathy is an important feature of classical Fabry disease, which results in alpha-galactosidase A deficiency and cellular globotriaosylceramide accumulation. We report the safety and efficacy of antiproteinuric therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) in a study of classical Fabry patients receiving recombinant agalsidase-beta therapy. METHODS AND DESIGN: The goal was maintenance of urine protein to creatinine ratio (UPCR) <0.5 g/g or a 50% reduction in baseline UPCR for 24 patients at eight study sites. The change in estimated glomerular filtration rate (eGFR) was assessed over 21 months of treatment. RESULTS: 18 out of 24 patients achieved the UPCR goal with eGFR slopes that were significantly better than six patients who did not achieve the UPCR goal (-3.6 (-4.8 to -1.1) versus -7.0 (-9.0 to -5.6) mL/min/1.73 m(2)/year, respectively, p=0.018). Despite achieving the UPCR goal, 67% (12/18 patients) still progressed with an eGFR slope <-2 mL/min/1.73 m(2)/year. Regression analysis showed that increased age at initiation of agalsidase-beta therapy was significantly associated with worsened kidney outcome. Hypotension and hyperkalaemia occurred in seven and eight patients, respectively, which required modification of antiproteinuric therapy but was not associated with serious adverse events. CONCLUSIONS: This study documents the effectiveness of agalsidase-beta (1 mg/kg/2 weeks) and antiproteinuric therapy with ACE inhibitors and/or ARB in patients with severe Fabry nephropathy. Patients had preservation of kidney function if agalsidase-beta treatment was initiated at a younger age, and UPCR maintained at or below 0.5 g/g with antiproteinuric therapy. TRIAL REGISTRATION NUMBER: NCT00446862.

From Theory to Practice: One Agency's Experience with Implementing an Evidence-Based Model.

As evidence-based practice is becoming integrated into children's mental health services as a means of improving outcomes for children and youth with severe behavioral and emotional problems, therapeutic foster care (TFC) which is a specialized treatment program for such youth, is one of few community-based programs considered to be evidence-based. "Together Facing the Challenge" (TFTC) which was developed as a component of a randomized trial of TFC has been identified as an evidence-based model. We describe the experiences reported by one of the agencies that participated in our study and how they have incorporated TFTC into their on-going practice. They highlight key implementation strategies, challenges faced, and lessons learned as they moved forward towards full implementation of TFTC throughout their agency.

Developmental programming: postnatal steroids complete prenatal steroid actions to differentially organize the GnRH surge mechanism and reproductive behavior in female sheep.

In female sheep, estradiol (E2) stimulates the preovulatory GnRH/LH surge and receptive behavior, whereas progesterone blocks these effects. Prenatal exposure to testosterone disrupts both the positive feedback action of E2 and sexual behavior although the mechanisms remain unknown. The current study tested the hypothesis that both prenatal and postnatal steroids are required to organize the surge and sex differences in reproductive behavior. Our approach was to characterize the LH surge and mating behavior in prenatally untreated (Control) and testosterone-treated (T) female sheep subsequently exposed to one of three postnatal steroid manipulations: endogenous E2, excess E2 from a chronic implant, or no E2 due to neonatal ovariectomy (OVX). All females were then perfused at the time of the expected surge and brains processed for estrogen receptor and Fos immunoreactivity. None of the T females exposed postnatally to E2 exhibited an E2-induced LH surge, but a surge was produced in five of six T/OVX and all Control females. No surges were produced when progesterone was administered concomitantly with E2. All Control females were mounted by males, but significantly fewer T females were mounted by a male, including the T/OVX females that exhibited LH surges. The percentage of estrogen receptor neurons containing Fos was significantly influenced in a brain region-, developmental stage-, and steroid-specific fashion by testosterone and E2 treatments. These findings support the hypothesis that the feedback controls of the GnRH surge are sensitive to programming by prenatal and postnatal steroids in a precocial species.

Arrhythmias in Fabry cardiomyopathy.

BACKGROUND: Prior studies suggest that the incidence of ventricular arrhythmias is high in patients with Fabry cardiomyopathy. This study evaluated the incidence of significant arrhythmias in a series of patients with Fabry cardiomyopathy. HYPOTHESIS: Arrhythmias are important causes of morbidity and mortality in Fabry Cardiomyopathy. METHODS: This study was a retrospective chart review of 19 patients with known Fabry cardiomyopathy. Device interrogation reports were reviewed for those who had implantable devices. Electrocardiogram, Holter monitor, and event monitors were reviewed in those who did not have implantable devices. RESULTS: Eighteen of nineteen patients were on enzyme replacement therapy (ERT). Nine (47%) out of 19 patients had implantable devices. Implant indications included symptomatic bradycardia, nonsustained ventricular tachycardia, conduction abnormalities, palpitations, and syncope. Mean follow-up in the patients with devices was 50 ± 23 months. Two patients received implantable cardioverter-defibrillator (ICD) shocks, 1 of which was inappropriate for atrial fibrillation. Patients were paced in the atrium 71% ± 37% of the time and paced in the ventricle 49% ± 52% of the time. Four patients with devices were paced more than 95% of the time. Patients with an ICD had lower heart rates prior to ICD implant than the group that did not have devices (60 ± 10 vs 78 ± 16, P = 0.03). Of the patients without devices, only 1 had sudden cardiac death. Patients with implanted devices had higher left ventricular (LV) mass indices compared to patients without implanted devices (136 ± 40 g/m(2) vs 93 ± 19 g/m(2), P = 0.008). CONCLUSIONS: Significant ventricular arrhythmias are uncommon in patients with Fabry cardiomyopathy on ERT, but utilization of pacing is high. Sudden cardiac death in Fabry cardiomyopathy may be related to bradycardia.

Chemical communication and reproduction in the gray short-tailed opossum (Monodelphis domestica).

The gray short-tailed opossum is one of the most widely studied of all marsupials and an important model for study of olfactory communication, particularly as it relates to pheromonal activation of reproduction. Males respond to differentially to female skin gland secretions and urine from anestrous females, while females respond only skin gland secretions, particularly that of the suprasternal gland. Divergent responses by male and female opossums to odors from these different body sources are most likely related to sex-specific production and deposition of chemical signals in this species. Female opossums do not have an estrous cycle but are stimulated to estrus by male pheromone. Females nuzzle scent marks from male suprasternal gland secretions, and thereby facilitate delivery of a nonvolatile estrus-inducing pheromone to the chemosensory epithelium of vomeronasal organ. Neuroendocrine correlates of pheromonal induction of estrus include elevated plasma estradiol and upregulation of progesterone receptors in hypothalamic regions that control reproductive behavior.

Organizational actions of postnatal estradiol in female sheep treated prenatally with testosterone: programming of prepubertal neuroendocrine function and the onset of puberty.

Prenatal testosterone (T) exposure defeminizes reproductive neuroendocrine function in female sheep, although the LH surge dysfunctions are initially less severe in gonadally intact females than in females subject to neonatal ovariectomy and estradiol (E) replacement. Because prepubertal ovarian production of E differs quantitatively and qualitatively from chronic E replacement, we tested the hypothesis that postnatal E exacerbates the consequences of prenatal T on the positive, but not the negative, steroid feedback controls of GnRH secretion. Our approach was to characterize prepubertal sensitivity to E negative feedback, the onset and maintenance of progestagenic cycles, and the LH surge response in ovary intact, prenatally untreated (control), and T-treated (T) sheep that were exposed postnatally to only endogenous E, or exposed to excess E by s.c. implant. Sensitivity to E negative feedback was reduced in T females, but excess postnatal E did not further increase LH pulse frequency. Excess E prevented ovarian cycles in several control females, and increased cycle irregularity in T females. However, the LH surge mechanism was functional in all control females (regardless of postnatal E exposure) and in some T females without excess E, but nonfunctional in T females with excess E. These findings suggest that postnatal E does not program increased resistance to E negative feedback, but excess postnatal E does disrupt other mechanisms required for ovarian cyclicity. We conclude that in this precocial species, prenatal steroids are sufficient to program controls of tonic LH secretion, but the LH surge mechanism is susceptible to further programming by postnatal E.

Behavioral and reproductive responses of female opossums to volatile and nonvolatile components of male suprasternal gland secretion.

Female gray short-tailed opossums (Monodelphis domestica) lack an estrous cycle and are induced into estrus by exposure to a pheromone in male scent marks. Behavioral and physiological responses of females to the volatile and nonvolatile components of scent marks were examined in two experiments. Young females (n=9) were tested prior to and during their first estrus for behavioral responses to scent marks, collected on a 7-ml glass vial rubbed over the suprasternal gland of a mature male. The response to volatile components of the scent mark, recorded when marked and unmarked vials were covered with a perforated shield, was compared to the response to these vials when unshielded. Estrous females nuzzled the shields over marked vials (55.8+/-8.5 nuzzles/10 min) more than the shielded clean vial (10.9+/-2.4) (P<0.05); a similar response was observed in anestrous females. Nuzzling of unshielded, scent-marked vials was higher (P<0.05) during anestrus than in the same females when in estrus. The role of nonvolatile pheromones in reproductive activation was tested in adult females (n=11) exposed for up to 14 days to a shielded, marked vial or to an unshielded, marked vial in a crossover design. All females exposed to unshielded vials expressed estrus, and 10 copulated. Only 2 females expressed estrus (significantly fewer, P<0.05), when exposed to shielded marked vials, and neither copulated. These results demonstrate that females detect and respond behaviorally to both volatile and nonvolatile components of male suprasternal gland secretion, but the estrus-inducing pheromone in these secretions is nonvolatile.

Sexual differentiation of the external genitalia and the timing of puberty in the presence of an antiandrogen in sheep.

Testicular steroids during midgestation sexually differentiate the steroid feedback mechanisms controlling GnRH secretion in sheep. To date, the actions of the estrogenic metabolites in programming neuroendocrine function have been difficult to study because exogenous estrogens disrupt maternal uterine function. We developed an approach to study the prenatal actions of estrogens by coadministering testosterone (T) and the androgen receptor antagonist flutamide, and tested the hypothesis that prenatal androgens program estradiol inhibitory feedback control of GnRH secretion to defeminize (advance) the timing of the pubertal increase in LH. Pregnant sheep were either untreated or treated with T, dihydrotestosterone (DHT) (a nonaromatizable androgen), or T plus flutamide from d 30-90 of gestation. To study the postnatal response to steroid negative feedback, lambs were gonadectomized and estradiol-replaced, and concentrations of LH were monitored in twice-weekly blood samples. Although T and DHT produced penile and scrotal development in females, the external genitalia of T plus flutamide offspring remained phenotypically female, regardless of genetic sex. Untreated females and females and males treated with T plus flutamide exhibited a pubertal increase in circulating LH at 26.4+/-0.5, 26.0+/-0.7, and 22.4+/-1.6 wk of age, respectively. In females exposed to prenatal androgens, the LH increase was advanced (T: 12.0+/-2.6 wk; DHT: 15.0+/-2.6 wk). These results demonstrate the usefulness of combining T and antiandrogen treatments as an approach to increasing prenatal exposure to estradiol. Importantly, the findings support our hypothesis that prenatal androgens program sensitivity to the negative feedback actions of estradiol and the timing of neuroendocrine puberty.

Efficacy of a parent-based sexual-risk prevention program for African American preadolescents: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of a parent-based sexual-risk prevention program for African American preadolescents. DESIGN: Randomized controlled trial. SETTING: Community-based study conducted in Athens, Georgia; Atlanta, Georgia; and Little Rock, Arkansas from 2001 to 2004. PARTICIPANTS: From 1545 inquiries, 1115 African American parent-preadolescent dyads (child, aged 9-12 years) formed the analytic sample. INTERVENTION: Participants were randomized into 1 of 3 study arms: enhanced communication intervention (five 2 1/2-hour sessions), single-session communication intervention (one 2 1/2-hour session), and general health intervention (control, one 2 1/2-hour session). OUTCOME MEASURES: Continuous measures of parent-preadolescent sexual communication and parental responsiveness to sex-related questions at preintervention, postintervention, and at 6- and 12-month follow-ups; and dichotomous measure of preadolescent sexual risk (having engaged in or intending to engage in sexual intercourse at 12-month follow-up). RESULTS: Using intent-to-treat participants, differences of mean change from baseline for continuous measures and relative risk for the dichotomous measure of sexual risk were calculated. Participants in the enhanced intervention had higher mean changes from baseline scores, indicating more sexual communication and responsiveness to sexual communication at each assessment after intervention for all continuous measures than those in the control intervention and single-session intervention. Preadolescents whose parents attended all 5 sessions of the enhanced intervention had a likelihood of sexual risk at the 12-month follow-up of less than 1.00 relative to those whose parents attended the control (relative risk, 0.65; 95% confidence interval, 0.41-1.03) and single-session (relative risk, 0.62; 95% confidence interval, 0.40-0.97) interventions. CONCLUSIONS: These results provide preliminary evidence for the efficacy of a parenting program designed to teach sexual communication skills to prevent sexual risk in preadolescents. TRIAL REGISTRATION; clinicaltrials.gov Identifier: NCT00137943.

Metabolism of daidzein by fecal bacteria in rats.

Daidzein (4',7-dihydroxyisoflavone), a soy phytoestrogen, is a weakly estrogenic compound that may have potential health benefits. Biotransformation of daidzein by the human gut microflora after ingestion converts it to either the highly estrogenic metabolite equol or to nonestrogenic metabolites. We investigated the metabolism of daidzein by colonic microflora of rats. Fecal samples, obtained before and after rats were exposed to daidzein at 250 or 1000 parts per million, were incubated in brain-heart infusion (BHI) broth with daidzein under anaerobic conditions. Samples were removed from the cultures daily and analyzed by high-performance liquid chromatography (HPLC) and mass spectrometry. The fecal bacteria of all rats, regardless of prior daidzein exposure, metabolized the added daidzein to dihydrodaidzein. Both compounds disappeared rapidly from BHI cultures incubated for more than 24 h, but no other daidzein metabolites were detected. Only daidzein and dihydrodaidzein were found in a direct analysis of the feces of rats that had consumed daidzein in their diets. Unlike the fecal bacteria of humans and monkeys, the rat flora rapidly metabolized daidzein to aliphatic compounds that could not be detected by HPLC or mass spectral analysis.

Antiproteinuric therapy and fabry nephropathy: sustained reduction of proteinuria in patients receiving enzyme replacement therapy with agalsidase-beta.

This report describes an open-label, nonrandomized, prospective evaluation of the effects of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy on patients who have Fabry disease and also received enzyme replacement therapy with agalsidase-beta, given at 1 mg/kg body wt every 2 wk. Previous placebo-controlled phase III and phase IV trials with agalsidase-beta demonstrated clearing of globotriaosylceramide from vascular endothelia but little effect on proteinuria or progressive loss of kidney function in patients with Fabry disease and severe chronic kidney disease marked by overt proteinuria and/or estimated GFR <60 ml/min per 1.73 m2. Angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker therapy is the standard of care for patients with proteinuric kidney diseases, but their use is challenging in patients with Fabry disease and low or low-normal baseline systemic BP. A group of patients with Fabry disease were treated with antiproteinuric therapy, in conjunction with agalsidase-beta; sustained reductions in proteinuria with stabilization of kidney function were achieved in a group of six patients who had severe Fabry nephropathy; the progression rate was -0.23 +/- 1.12 ml/min per 1.73 m2 per yr with 30 mo of follow-up.

Heparin binding EGF is necessary for vasospastic response to endothelin.

Endothelin-1 (ET-1), a powerful vasoconstrictor, is involved in vasospastic diseases such as coronary artery disease and subarachnoidal hemorrhage, as well as in renal and cardiovascular fibrotic remodeling. Transactivation of the epidermal growth factor receptor (EGFR) mediates ET-1 signaling in vascular smooth muscle cells (VSMCs) and isolated arteries. Moreover, EGFR is required for a full constrictive response to ET-1. However, the relevant mechanisms mediating EGFR transactivation in response to ET-1 have not been identified. The present study used isolated arteries and VSMCs to investigate the role of the EGFR ligand heparin binding-epidermal growth factor (HB-EGF) in ET-1-induced transactivation of EGFR, intracellular calcium mobilization, and VSMCs contraction. While baseline blood pressures were similar in HB-EGF-deficient and in wild-type littermate mice, the vasoconstrictor actions of ET-1 were attenuated in HB-EGF-/- animals. In isolated mouse carotid artery segments mounted in an arteriograph, ET-1 caused only a weak increase in isovolumetric tone in HB-EGF-deficient vessels, and this effect was mimicked by inhibition of EGFR tyrosine kinase or phosphoinositide 3-kinase (PI3K) in wild-type arteries with or without endothelium, indicating a specific role in VSMCs. EGFR or PI3K inhibitors had no effect on KCl-induced contraction, which was normal in HB-EGF-deficient mice. To confirm that the abnormal responses in HB-EGF-deficient mice were due to impaired EGFR signaling, we studied VSMCs from waved-2 (wa2) mice; these animals have a mutation causing a partial loss of function of EGFR tyrosine kinase activity. The ET-1-induced calcium peak was reduced by 30% in VSMCs from wa2 mice and from HB-EGF-/- mice. This effect was reproduced by preincubation of wild-type VSMCs with EGFR inhibitor AG1478 and PI3K inhibitors LY294002 and wortmannin. ProHB-EGF is bound to the cell membrane and released after cleavage by metalloproteinases; its action may contribute to effects of GPCR agonists on cell growth. Pretreatment of mouse VSMCs with batimastat, a metalloproteinase inhibitor, significantly attenuated ET-1-induced [Ca(2+)](i) response in wild-type cells. Human proHB-EGF has been shown to be the endogenous receptor for Corynebacterium diphteriae toxin (DT). Mutated DT toxin (CRM197) is devoid of toxicity but it neutralizes HB-EGF binding to EGFR. Pretreatment of human VSMCs from internal mammary arteries with CRM197 significantly blunted ET-1-stimulated calcium transients. In conclusion, these findings suggest that the mechanism of ET-1-induced vasoconstriction involves HB-EGF-mediated transactivation of the EGFR. This functional cascade requires modulation of agonist-induced calcium transient by EGFR and PI3K with extremely fast kinetics, suggesting a novel paradigm for GPCR-mediated calcium signaling, which may offer future therapeutic targets.

Long-term exposure of female sheep to physiologic concentrations of estradiol: effects on the onset and maintenance of reproductive function, pregnancy, and social development in female offspring.

As steroids and steroid-like compounds accumulate in the environment, it has become important to understand how low-dose exposure affects reproductive function. Ovary-intact sheep were used in a multigenerational study, to determine whether chronic exposure to low levels of estrogen disrupts reproductive function and behavior. We assessed parameters of reproductive performance in control and postnatally estradiol-treated females (Generation 1, G1), and their offspring (Generation 2, G2). In the G1 animals, 17beta-estradiol (E) was administered continuously from 4 wk of age at two doses via subcutaneous implants (ultralow E [<1 pg/ml in circulation, n = 8] or low E [1-3 pg/ml, n = 8]). Both doses delayed puberty; low E also produced pronounced prepubertal and seasonal anestrus hypogonadotropism, and delayed the onset of the second breeding season. All G1 animals conceived and produced offspring (G2), the treatment of which resulted from continuous maternal exposure during pregnancy and lactation. Behavioral observations of G2 females revealed that low prenatal E modestly masculinized play behavior and increased the frequency of attempts to displace competitors relative to ultralow E and control animals. The timing and magnitude of the LH surge also differed in prepubertal low prenatal E females relative to the controls, although these differences were not evident when retested at one year of age. These findings support the hypothesis that chronic exposure to physiologic amounts of exogenous estrogens has multigenerational effects on behavior and neuroendocrine function. Despite these disruptive steroid actions, ovarian cyclicity and fertility are not invariably compromised, pointing to an impressive resiliency of the reproductive axis to insult by exogenous estrogenic compounds.

Programming of GnRH feedback controls timing puberty and adult reproductive activity.

The timing of puberty generally differs between sexes, and this may be due to sex differences in the organization of steroid feedback systems. We propose that the reproductive neuroendocrine default sex is female. If the individual is male, the feedback control of GnRH secretion is programmed early in development, and the pubertal GnRH rise is either advanced or delayed depending upon species. This developmental programming is by androgens. Early programming also reorganizes adult reproductive neuroendocrine function to change a pattern of cyclic gamete release (periodic ovulations) requiring multiple feedback systems to that of a continuous one (spermatogenesis) requiring only the negative feedback control. The multiple feedback systems underlying the complex ovulatory cycle are innate, and in the male the unnecessary feedbacks are abolished or rendered less sensitive during development by the estrogenic, as well as the androgenic metabolites of testosterone.

Osmoregulatory effects of hypophysectomy and homologous prolactin replacement in hybrid striped bass.

The effects of ovine prolactin (oPRL) and striped bass prolactin (sbPRL; Morone saxatilis) on plasma osmolality, electrolyte balance, and gill Na(+),K(+)-ATPase activity were investigated in hypophysectomized (Hx), freshwater (FW)-acclimated, hybrid striped bass (M. saxatilisxMorone chrysops). They were kept in dilute (isoosmotic) seawater for about 10 days after surgery. Seven days after transfer to FW, Hx fish had lower plasma osmolality and lower levels of Na(+), Cl(-), and Ca(2+) than sham-operated and intact fish. Fish were injected four times with oPRL (1, 5, or 20 microg/g body mass), sbPRL (10 or 100 ng/g), or hormone vehicle (0.9% NaCl) at 48-h intervals (days 0, 2, 4, and 6) in FW and then sampled for blood plasma 24 h after the fourth injection (day 7). In Hx fish, oPRL (5 and 20 microg/g) and sbPRL (10 and 100 ng/g) were effective in maintaining plasma osmolality and levels of Na(+), Cl(-), and Ca(2+) above values seen in saline-injected controls. Hypophysectomy did not affect branchial Na(+),K(+)-ATPase activity, but enzyme activity was significantly reduced in Hx fish receiving oPRL (20 mug/g) or sbPRL (10 or 100 ng/g). These results indicate that PRL acts to maintain plasma osmotic and ionic balance in FW-adapted hybrid striped bass, and that this may involve downregulation of branchial Na(+),K(+)-ATPase activity.

Heparin-binding epidermal growth factor-like growth factor links hepatocyte priming with cell cycle progression during liver regeneration.

The mechanisms that regulate the transition between the initial priming phase and DNA replication in liver regeneration are poorly understood. To study this transition, we compared events occurring after standard two-thirds partial hepatectomy, which elicits full regeneration, with response to a reduced hepatectomy, one-third partial hepatectomy (1/3PH), which leads to little DNA replication. Although the initial response to partial hepatectomy at the priming phase appeared to be similar between the two procedures, cell cycle progression was significantly blunted in 1/3PH mice. Among the main defects observed in 1/3PH mice were an almost complete deficiency in retinoblastoma phosphorylation and the lack of increase in kinase activity associated with cyclin E. We report that, in two-thirds partial hepatectomy mice, the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) preceded the start of DNA replication and was not detectable in 1/3PH animals. Injection of HB-EGF into 1/3PH mice resulted in a >15-fold increase in DNA replication. Moreover, we show that hepatocyte DNA replication was delayed in HB-EGF knock-out mice. In summary, we show that HB-EGF is a key factor for hepatocyte progression through G(1)/S transition during liver regeneration.

Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle.

Stimulation of alpha1-adrenoceptors induces proliferation of vascular smooth muscle cells (SMCs) and contributes to arterial remodeling. Although activation of NAD(P)H oxidase and generation of reactive oxygen species (ROS) are required, little is known about this pathway. In this study, we examined the hypothesis that epidermal growth factor receptor (EGFR) transactivation and extracellular regulated kinases (ERK) are involved in alpha1-adrenoceptor-mediated SMC growth. Phenylephrine increased protein synthesis in association with a rapid (< or =5 minutes) and sustained (> or =60 minutes) doubling of phosphorylation of EGFR and ERK1/2, but not p38 or JNK in the media of rat aorta maintained in organ culture. Antagonists of EGFR phosphotyrosine activity (AG-1478) and ERK phosphorylation (PD-98059, U-0126) abolished phenylephrine-induced protein synthesis, whereas antagonists of p38 or JNK phosphorylation had no specific effect. A competitive antagonist (P22) for heparin binding EGF-like growth factor (HB-EGF) blocked phenylephrine-induced protein synthesis, as did downregulation of pro-HB-EGF (CRM197). Phenylephrine-induced protein synthesis was inhibited by neutralizing antibody to HB-EGF and absent in HB-EGF-/- SMCs. Inhibitors of metalloproteinases (BiPS, KB-R7785) also blocked adrenergic growth. The neutralizing antibody against HB-EGF had no effect on the two-fold increase in ROS generation induced by phenylephrine (DCF fluorescence), suggesting that stimulation of NAD(P)H oxidase by alpha1-adrenoceptor occupation precedes HB-EGF release. Cell culture studies confirmed and extended these findings. These data suggest that alpha1-adrenoceptor-mediated SMC growth requires ROS-dependent shedding of HB-EGF, transactivation of EGFR, and activation of the MEK1/2-dependent MAP kinase pathway. This trophic pathway may link sympathetic activity to arterial wall growth in adaptive remodeling and hypertrophic disease.