Arteries and veins are specified by antagonistic transcriptional programs. However, during development and regeneration, new arteries can arise from pre-existing veins through a poorly understood process of cell fate conversion. Here, using single-cell RNA sequencing and mouse genetics, we show that vein cells of the developing heart undergo an early cell fate switch to create a pre-artery population that subsequently builds coronary arteries. Vein cells underwent a gradual and simultaneous switch from venous to arterial fate before a subset of cells crossed a transcriptional threshold into the pre-artery state. Before the onset of coronary blood flow, pre-artery cells appeared in the immature vessel plexus, expressed mature artery markers, and decreased cell cycling. The vein-specifying transcription factor COUP-TF2 (also known as NR2F2) prevented plexus cells from overcoming the pre-artery threshold by inducing cell cycle genes. Thus, vein-derived coronary arteries are built by pre-artery cells that can differentiate independently of blood flow upon the release of inhibition mediated by COUP-TF2 and cell cycle factors.

The discovery that atypical chemokine receptors (ACKRs) can initiate alternative signaling pathways rather than classical G-protein coupled receptor (GPCR) signaling has changed the paradigm of chemokine receptors and their roles in modulating chemotactic responses. The ACKR family has grown over the years, with discovery of new functions and roles in a variety of pathophysiological conditions. However, the extent to which these receptors regulate normal physiology is still continuously expanding. In particular, atypical chemokine receptor 3 (ACKR3) has proven to be an important receptor in mediating normal biological functions, including cardiac development and migration of cortical neurons. In this review, we illustrate the versatile and intriguing role of ACKR3 in physiology.

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Uteroplacental development is a crucial step facilitating conceptus growth. Normal placental development comprises extensive placental angiogenesis to support fetoplacental transport, meeting the metabolic demands of the fetus. Compromised pregnancies due to maternal stressors such as over or undernutrition, maternal age or parity, altered body mass index, or genetic background result in altered vascular development of the placenta. This negatively affects placental growth and placental function and ultimately results in poor pregnancy outcomes. Nonetheless, the placenta acts as a sensor to the maternal stressors and undergoes modifications, which some have termed placental programming, to ensure healthy development of the conceptus. Sex steroid hormones such as estradiol-17β and progesterone, chemokines such as chemokine ligand 12, and angiogenic/vasoactive factors such as vascular endothelial growth factors, placental growth factor, angiopoietins, and nitric oxide regulate uteroplacental development and hence are often used as therapeutic targets to rescue compromised pregnancies. Interestingly, the presence of sex steroid receptors has been identified in the fetal membranes (developing fetal placenta). Environmental steroid mimetics known as endocrine disrupting compounds disrupt conceptus development and lead to transgenerational impairments by epigenetic modification of placental gene expression, which is another area deserving intense research efforts. This review attempts to summarize current knowledge concerning intrinsic and extrinsic factors affecting selected reproductive functions with the emphasis on placental development.

Successful embryo implantation is a complex and highly regulated process involving precise synchronization between the fetal-derived trophoblast cells and maternal uterine luminal epithelium. Multiple endocrine-driven factors are important for controlling the timely receptivity of the uterus, and this complexity underscores implantation failure as a major cause of recurrent infertility associated with assisted reproductive technologies. One particular cellular structure often hypothesized to promote receptivity is the pinopode or uterodome -a hormonally regulated, large cellular protrusion on the uterine epithelial surface. Recent clinical studies associate pinopodes with favorable fertility outcomes in women, and because they are directly linked to an increase in progesterone levels, the potential utility of these hormone-regulated cell biological structures in predicting or improving implantation in a clinical setting holds promise. In this review, we aim to generate interest in pinopodes from the broader cell biology and endocrinology communities, re-examine methodologies in pinopode research, and identify priorities for future investigation of pinopode structure and function in women's reproductive health.