A critical role for thioredoxin-interacting protein in diabetes-related impairment of angiogenesis.

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose-mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose-induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.

Numb is required for the production of terminal asymmetric cell divisions in the developing mouse retina.

In the developing nervous system, cell diversification depends on the ability of neural progenitor cells to divide asymmetrically to generate daughter cells that acquire different identities. While much work has recently focused on the mechanisms controlling self-renewing asymmetric divisions producing a differentiating daughter and a progenitor, little is known about mechanisms regulating how distinct differentiating cell types are produced at terminal divisions. Here we study the role of the endocytic adaptor protein Numb in the developing mouse retina. Using clonal numb inactivation in retinal progenitor cells (RPCs), we show that Numb is required for normal cell-cycle progression at early stages, but is dispensable for the production of self-renewing asymmetric cell divisions. At late stages, however, Numb is no longer required for cell-cycle progression, but is critical for the production of terminal asymmetric cell divisions. In the absence of Numb, asymmetric terminal divisions that generate a photoreceptor and a non-photoreceptor cell are decreased in favor of symmetric terminal divisions generating two photoreceptors. Using live imaging in retinal explants, we show that a Numb fusion protein is asymmetrically inherited by the daughter cells of some late RPC divisions. Together with our finding that Numb antagonizes Notch signaling in late-stage RPCs, and that blocking Notch signaling in late RPCs almost completely abolishes the generation of terminal asymmetric divisions, these results suggest a model in which asymmetric inheritance of Numb in sister cells of terminal divisions might create unequal Notch activity, which in turn drives the production of terminal asymmetric divisions.

Minireview: rapid actions of sex steroids in the endothelium.

The endothelium is a dynamic interface between the blood vessel and the circulating blood that plays a pivotal role in vascular homeostasis. As such, studies on sex steroid regulation of endothelial function are critical to understanding the role of sex steroids in cardiovascular health and disease. The classical model of steroid action involves liganded steroid receptors binding to specific response elements on target genes to regulate gene transcription. In whole organisms, the time lag between steroid administration and observable effects produced by newly synthesized protein is typically in the order of hours to days. And yet, some effects of steroids, such as vasodilatation, occur within seconds to minutes of steroid administration. Studies in multiple cell types have also shown that steroids can cause the rapid initiation of multiple signaling cascades and second messenger systems, prompting investigations into alternate, transcription independent mechanisms of steroid action. Studies of the endothelium over the past two decades have revealed fundamental mechanisms in rapid sex steroid signaling. In particular, endothelium-dependent vasodilatation by estradiol-induced activation of endothelial nitric oxide synthase has proven to be an uniquely informative model to study sex steroid signaling via classical sex steroid receptors localized to the cell membrane. Despite the complexity of feedback and cross talk between rapid sex steroid signaling and other modes of steroid action, recent studies in this field are facilitating the development of steroidal drugs that selectively target the ability of sex steroids to initiate signaling cascades.

Androgens, angiogenesis and cardiovascular regeneration.

PURPOSE OF REVIEW: Striking sex differences exist not only in the incidence of cardiovascular disease, but also in the clinical outcomes. Although cardiovascular events occur earlier in men, in women, it appears they have poorer short-term and long-term outcomes following these events compared to men. Thus, intrinsic sex differences may exist not only in atherogenesis, but also with respect to cardiovascular adaptation/repair in response to ischemia and/or infarction. Angiogenesis, the growth of new blood vessels, is essential for organ development and is critical to cardiovascular repair/regeneration. Although the effect of estrogen on angiogenesis has been studied extensively, the role of androgens has remained largely unexplored. RECENT FINDINGS: Multiple lines of evidence now suggest an important role for androgens in cardiovascular repair and regeneration. Studies suggest that androgens stimulate angiogenesis via vascular endothelial growth factor-related mechanisms and by the stimulation of erythropoietin production. Furthermore, endothelial progenitor cells, important in angiogenesis, appear to be hormonally regulated and an important target of androgen action. SUMMARY: Given the age-related decline in androgens, the findings discussed here have implications for therapeutic angiogenesis and androgen replacement therapies in aging and hypogonadal men.

A sex-specific role for androgens in angiogenesis.

Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.