TGF-β Signaling Is Necessary and Sufficient for Pharyngeal Arch Artery Angioblast Formation

The pharyngeal arch arteries (PAAs) are transient embryonic blood vessels that mature into critical segments of the aortic arch and its branches. Although defects in PAA development cause life-threating congenital cardiovascular defects, the molecular mechanisms that orchestrate PAA morphogenesis remain unclear. Through small-molecule screening in zebrafish, we identified TGF-β signaling as indispensable for PAA development. Specifically, chemical inhibition of the TGF-β type I receptor ALK5 impairs PAA development because nkx2.5+ PAA progenitor cells fail to differentiate into tie1+ angioblasts. Consistent with this observation, we documented a burst of ALK5-mediated Smad3 phosphorylation within PAA progenitors that foreshadows angioblast emergence. Remarkably, premature induction of TGF-β receptor activity stimulates precocious angioblast differentiation, thereby demonstrating the sufficiency of this pathway for initiating the PAA progenitor to angioblast transition. More broadly, these data uncover TGF-β as a rare signaling pathway that is necessary and sufficient for angioblast lineage commitment

Consort diagrams for the final analytical samples for incident storage, voiding LUTS, depression and anxiety in a community cohort of Australian men.

<p>Consort diagrams for the final analytical samples for incident storage, voiding LUTS, depression and anxiety in a community cohort of Australian men.</p

Baseline characteristics and multi-stage regression estimates for incident depression & anxiety (diagnosed/symptomatic/medications) in a community-based cohort of Australian men.

<p><i>Data presented are mean & standard deviation (continuous) or percentage & number (categorical)</i>. <i>Non-normally distributed data are presented as median & SEM</i>.</p><p>* <i>Model 1 includes all covariates with a univariate association with the outcome measure of p<0</i>.<i>25</i></p><p>^<i>#</i><i>Identical to Model 1</i>, <i>excluding inflammation markers with a univariate association of p<0</i>.<i>25</i>.</p><p>^<i>Δ</i><i>Identical to Model 1</i>, <i>excluding LUTS and depression or anxiety</i>. <i>Full model also adjusted for</i>: <i>(Depression) age category</i>, <i>BMI</i>, <i>handgrip strength</i>, <i>marital status</i>, <i>work status</i>, <i>household income</i>, <i>recreational exercise level</i>, <i>total testosterone</i>, <i>erectile function</i>, <i>solitary and dyadic sexual desire</i>, <i>sleep apnea (AHI>10)</i>, <i>angina</i>, <i>diabetes; (Anxiety) As previous</i>, <i>minus handgrip strength</i>, <i>sexual desire</i>, <i>diabetes</i>, <i>also</i>: <i>systolic BP</i>, <i>serum prostate specific antigen (PSA)</i>, <i>see</i>: <i>S</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137903#pone.0137903.s002" target="_blank">2</a><i>Table for confounder univariate and multivariate data)</i>.</p><p>Baseline characteristics and multi-stage regression estimates for incident depression & anxiety (diagnosed/symptomatic/medications) in a community-based cohort of Australian men.</p

Baseline characteristics and multi-stage regression estimates for incident storage and voiding LUTS (AUA-SI) in a community-based cohort of Australian men.

<p>Data presented are mean & standard deviation (continuous) or percentage & number (categorical). Non-normally distributed data are presented as median & SEM.</p><p>* Model 1 includes all covariates with a univariate association with the outcome measure of p<0.25</p><p>^# Identical to Model 1, excluding inflammation markers with a univariate association of p<0.25.</p><p>^Δ Identical to Model 1, excluding LUTS, anxiety & depression. Full model also adjusted for: (Storage LUTS) age, BMI, handgrip strength, marital status, work status, household income, recreational exercise level, LDL cholesterol, total testosterone, sleep apnea (AHI>10), diabetes; (Voiding LUTS) As previous, minus work status, LDL cholesterol, also: HDL cholesterol, serum prostate specific antigen (PSA), erectile dysfunction, angina (see: <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0137903#pone.0137903.s001" target="_blank">S1 Table</a> for confounder univariate and multivariate data).</p><p>Baseline characteristics and multi-stage regression estimates for incident storage and voiding LUTS (AUA-SI) in a community-based cohort of Australian men.</p

Effect of medications at baseline (2002–5) and follow-up (2007–10) on incident storage, voiding LUTS, and common mental health disorder (CMHD; anxiety / depression) in a community-dwelling cohort of men.

<p><i>Data presented are OR (95% CI) from binomial regression of incident storage and voiding LUTS (AUA-SI; referent category</i>: <i>no storage / voiding LUTS) & incident depression and anxiety (self-reported physician diagnosis & symptomatic depression (BDI-1a) and anxiety (PHQ–9)</i>. <i>Medication usage assessed through Pharmaceutical Benefits Scheme linkage</i>. <i>Data include those men who were found to take selected medications up to 6 months prior to initial visit (baseline)</i>, <i>had ceased taking selected medications between baseline and follow-up (+/-)</i>, <i>those who had commenced taking selected medications after baseline visit and up to 6 months prior to follow-up visit (-/-)</i>, <i>and those who were found to have not used the selected medications (-/-; exposure referent category)</i>.</p><p>Effect of medications at baseline (2002–5) and follow-up (2007–10) on incident storage, voiding LUTS, and common mental health disorder (CMHD; anxiety / depression) in a community-dwelling cohort of men.</p