Arteries of the Lower Limb-Embryology, Variations, and Clinical Significance.

OBJECTIVES: The purpose of this article is to review the embryology of the lower limb arterial anatomy along with common variants and their clinical relevance. DESIGN: Embryologic variations of the lower limb arterial system may be explained by i.) persistence of primordial arterial segments, ii.) abnormal fusion, iii.) segmental hypoplasia/absence, or a combination of both. Persistent sciatic artery, corona mortis, and popliteal entrapment syndrome will also be discussed with associated symptoms, and potential complications. CONCLUSION: Knowledge of these variations is essential for surgical and endovascular management as failure to recognize them can result in complications.

Parallels between the Developing Vascular and Neural Systems: Signaling Pathways and Future Perspectives for Regenerative Medicine.

Neurovascular disorders, which involve the vascular and nervous systems, are common. Research on such disorders usually focuses on either vascular or nervous components, without looking at how they interact. Adopting a neurovascular perspective is essential to improve current treatments. Therefore, comparing molecular processes known to be involved in both systems separately can provide insight into promising areas of future research. Since development and regeneration share many mechanisms, comparing signaling molecules involved in both the developing vascular and nervous systems and shedding light to those that they have in common can reveal processes, which have not yet been studied from a regenerative perspective, yet hold great potential. Hence, this review discusses and compares processes involved in the development of the vascular and nervous systems, in order to provide an overview of the molecular mechanisms, which are most promising with regards to treatment for neurovascular disorders. Vascular endothelial growth factor, semaphorins, and ephrins are found to hold the most potential, while fibroblast growth factor, bone morphogenic protein, slits, and sonic hedgehog are shown to participate in both the developing vascular and nervous systems, yet have not been studied at the neurovascular level, therefore being of special interest for future research.

Tmem100-BAC-EGFP mice to selectively mark and purify embryonic endothelial cells of large caliber arteries in mid-gestational vascular formation.

Embryonic vascular development is achieved through the complex arrays of differentiation, proliferation, migration and mutual interaction of different cell types, and visualization as well as purification of unique cell populations are fundamental in studying its detailed mechanisms using in vivo experimental models. We previously demonstrated that Tmem100 was a novel endothelial gene encoding a small transmembrane protein, and that Tmem100 null mice showed embryonic lethality due to severe impairment of vascular formation. In the present study, we generated an EGFP reporter mouse line using a 216 kb genomic region containing mouse Tmem100 gene. A novel line designated as Tmem100-BAC-EGFP mice precisely recapitulated the Tmem100 expression profile at the mid-gestational stage, which was highly enriched in endothelial cells of large caliber arteries in mouse embryos. FACS experiments demonstrated that Tmem100-BAC-EGFP mice served to selectively purify a specific population of arterial endothelial cells, indicating their usefulness not only for the research concerning Tmem100 expression and function but also for comparative analysis of multiple endothelial cell subgroups in embryonic vascular development.

The Many Faces of Persistent Stapedial Artery: CT Findings and Embryologic Explanations.

Persistent stapedial artery is a vascular anomaly with both clinical and surgical implications. Because of its scarcity, however, it remains underrecognized on imaging. Presented here is a series of 10 cases, demonstrating characteristic CT findings associated with this vascular anomaly and its most common pathognomonic imaging signs. The variable morphologic configurations and their corresponding embryologic underpinnings are described. Clinical and surgical implications of this rare anomaly are discussed.

Pharyngeal pouches provide a niche microenvironment for arch artery progenitor specification.

The paired pharyngeal arch arteries (PAAs) are transient blood vessels connecting the heart with the dorsal aorta during embryogenesis. Although PAA malformations often occur along with pharyngeal pouch defects, the functional interaction between these adjacent tissues remains largely unclear. Here, we report that pharyngeal pouches are essential for PAA progenitor specification in zebrafish embryos. We reveal that the segmentation of pharyngeal pouches coincides spatiotemporally with the emergence of PAA progenitor clusters. These pouches physically associate with pharyngeal mesoderm in discrete regions and provide a niche microenvironment for PAA progenitor commitment by expressing BMP proteins. Specifically, pouch-derived BMP2a and BMP5 are the primary niche cues responsible for activating the BMP/Smad pathway in pharyngeal mesoderm, thereby promoting progenitor specification. In addition, BMP2a and BMP5 play an inductive function in the expression of the cloche gene npas4l in PAA progenitors. cloche mutants exhibit a striking failure to specify PAA progenitors and display ectopic expression of head muscle markers in the pharyngeal mesoderm. Therefore, our results support a crucial role for pharyngeal pouches in establishing a progenitor niche for PAA morphogenesis via BMP2a/5 expression.

A symptomatic atherosclerotic persistent pharyngo-hyo-stapedial artery: Treatment management and embryological considerations.

The stapedial artery (SA) is an embryonic vessel connecting the internal carotid artery (ICA) to the branches of the future external carotid artery (ECA). It passes through the primordium of the stapes that progressively develops around the SA. Normally, SA disappears during the tenth week in utero. Approximately 0.4% of the population can have a persistent SA. It can persist as four types of embryological variations, of which the pharyngo-hyo-stapedial variant has been rarely described before. We reported a case of a 61-year-old woman presented with transient ischemic attacks (TIAs). Computed tomography angiography showed an unusual "duplicated" aspect of the left ICA. Digital subtraction angiography depicted a persistent pharyngo-hyo-stapedial artery with an atherosclerotic wall and was considered the cause of the TIAs. After failure of the antiplatelet therapy in preventing recurrent TIAs, stenting of the artery was planned and successfully performed. Patient was asymptomatic during 12-month follow-up. The pharyngo-hyo-stapedial artery is a very rare variation in which the SA is supplied by the inferior tympanic (rising from the ascending pharyngeal artery) and the hyoid artery (rising from the ICA). To our knowledge, this is a unique case of a pharyngo-hyo-stapedial artery in a patient presenting associated ischemic symptoms. Radiological and embryological findings are discussed.

An unusual case of primate arterial pattern in a human upper limb / Un caso inusual de patrón arterial de primates en un miembro superior humano

During routine undergraduate dissections of the upper limb, variations on the usual arterial and muscular patterns were observed in a 68 year-old male cadaver. The arterial and muscular pattern found in our specimen is similar to that of some primates in the following terms. 1) Brachial artery duplicity, on the right side, with a superficial brachio-ulnoradial artery. 2) In the right upper limb, the biceps brachii muscle continued with the superficial muscles of the forearm. 3) The brachial artery on the left side, cross over in front of the median nerve, as the only artery of the arm with a network axillary pattern. 4) On both sides, the ulnar artery was superficial and originated at the elbow from superficial brachial arteries. 5) The right anterior interosseous artery intervened in the vascularization of the hand. These results suggest that this may be a case of early detention of human embryonic development and/or the persistence of phylogenetic older patterns. In the literature, we have found no reference to the presence of all these variations in the same individual. The objective of our study was to analyze these variations from an embryological and phylogenetic perspective.

Durante las disecciones de pregrado de rutina del miembro superior, se observaron variaciones en los patrones arteriales y musculares habituales en un cadáver macho de 68 años. El patrón arterial y muscular que se encuentra en nuestro espécimen es similar al de algunos primates en los siguientes términos. 1) Duplicidad de la arteria braquial, en el lado derecho, con una arteria braquioulnoradial superficial. 2) En el miembro superior derecho, el músculo bíceps braquial continuó con los músculos superficiales del antebrazo. 3) La arteria braquial en el lado izquierdo, se cruza frente al nervio mediano, como la única arteria del brazo con un patrón axilar en red. 4) En ambos lados, la arteria ulnar era superficial y se originó en el codo de las arterias braquiales superficiales. 5) La arteria interósea anterior derecha intervino en la vascularización de la mano. Estos resultados sugieren que este puede ser un caso de detención temprana del desarrollo embrionario humano y/o la persistencia de patrones filogenéticos más antiguos. En la literatura, no hemos encontrado ninguna referencia a la presencia de todas estas variaciones en el mismo individuo. El objetivo de nuestro estudio fue analizar estas variaciones desde una perspectiva embriológica y filogenética.

Descriptive and topographical analysis of the labyrinthine artery in human fetuses.

Hearing or/and balance impairments may be caused by disorders of the labyrinthine artery (LA) and their branches. Most findings regarding the LA anatomy have been acquired through investigation of the cerebellopontine angle (CPA) in animal or adult human specimens. Eighty-eight CPAs and LAs of human fetuses were investigated using angio-techniques and microdissections. We found 15 intricate forms of distribution of LA. The LA usually originated from the extra-meatus loop in the anterior inferior cerebellar artery (AICA). The distribution of its terminal branches was 53.42% uni-arterial, 44.31% bi-arterial, and 2.27% tri-arterial systems. In the uni-arterial system, the LA described an anterior superior path to the cochlear nerve (CN) and originated its terminal branches in the gap between CN and the inferior part of the vestibular nerve. In the bi-arterial system, the anterior LA was located anterior and superior to the CN while the posterior LA appeared posterosuperior to the superior part of the vestibular nerve. In the tri-arterial system, the terminal branches originated directly from the AICA loop. Our results provide anatomical support to explain how compressions in the LA branches inside the internal acoustic meatus, as evoked by Schwannomas in the VII and VIII nerves, can lead to hearing and balance loss. The zone of the posterior vestibular nerve appeared to be a "safe area" for invasive procedures in these specimens.

NFAT5 promotes arteriogenesis via MCP-1-dependent monocyte recruitment.

Studies have demonstrated that nuclear factor of activated T cells 5 (NFAT5) is not only a tonicity-responsive transcription factor but also activated by other stimuli, so we aim to investigate whether NFAT5 participates in collateral arteries formation in rats. We performed femoral artery ligature (FAL) in rats for hindlimb ischaemia model and found that NFAT5 was up-regulated in rat adductors with FAL compared with sham group. Knockdown of NFAT5 with locally injection of adenovirus-mediated NFAT5-shRNA in rats significantly inhibited hindlimb blood perfusion recovery and arteriogenesis. Moreover, NFAT5 knockdown decreased macrophages infiltration and monocyte chemotactic protein-1 (MCP-1) expression in rats adductors. In vitro, with interleukin-1ß (IL-1ß) stimulation and loss-of-function studies, we demonstrated that NFAT5 knockdown inhibits MCP-1 expression in endothelial cells and chemotaxis of THP-1 cells regulated by ERK1/2 pathway. More importantly, exogenous MCP-1 delivery could recover hindlimb blood perfusion, promote arteriogenesis and macrophages infiltration in rats after FAL, which were depressed by NFAT5 knockdown. Besides, NFAT5 knockdown also inhibited angiogenesis in gastrocnemius muscles in rats. Our results indicate that NFAT5 is a critical regulator of arteriogenesis and angiogenesis via MCP-1-dependent monocyte recruitment, suggesting that NFAT5 may represent an alternative therapeutic target for ischaemic diseases.

The mouse fetal-placental arterial connection: A paradigm involving the primitive streak and visceral endoderm with implications for human development.

In Placentalia, the fetus depends upon an organized vascular connection with its mother for survival and development. Yet, this connection was, until recently, obscure. Here, we summarize how two unrelated tissues, the primitive streak, or body axis, and extraembryonic visceral endoderm collaborate to create and organize the fetal-placental arterial connection in the mouse gastrula. The primitive streak reaches into the extraembryonic space, where it marks the site of arterial union and creates a progenitor cell pool. Through contact with the streak, associated visceral endoderm undergoes an epithelial-to-mesenchymal transition, contributing extraembryonic mesoderm to the placental arterial vasculature, and to the allantois, or pre-umbilical tissue. In addition, visceral endoderm bifurcates into the allantois where, with the primitive streak, it organizes the nascent umbilical artery and promotes allantoic elongation to the chorion, the site of fetal-maternal exchange. Brachyury mediates streak extension and vascular patterning, while Hedgehog is involved in visceral endoderm's conversion to mesoderm. A unique CASPASE-3-positive cell separates streak- and non-streak-associated domains in visceral endoderm. Based on these new insights at the posterior embryonic-extraembryonic interface, we conclude by asking whether so-called primordial germ cells are truly antecedents to the germ line that segregate within the allantois, or whether they are placental progenitor cells. Incorporating these new working hypotheses into mutational analyses in which the placentae are affected will aid understanding a spectrum of disorders, including orphan diseases, which often include abnormalities of the umbilical cord, yolk sac, and hindgut, whose developmental relationship to each other has, until now, been poorly understood. This article is categorized under: Birth Defects > Associated with Preimplantation and Gastrulation Early Embryonic Development > Gastrulation and Neurulation.

[The functions of arterial sympathetic innervation: from development to pathology]. / Les fonctions de l'innervation sympathique artérielle - Du développement à la pathologie.

Arterial sympathetic innervation (ASI) is a complex biological process requiring a fine axonal guidance by arteries. Its physiological impact has remained unknown for decades but recently started to be better understood and recognized. ASI is a key element of the adaptive response of the cardiovascular system to challenging situations (exposure to cold, exercise…) as ASI controls the diameter of resistance arteries, thus blood supply to organs and systemic arterial blood pressure via arterial tone modulation. Defaults in ASI can lead to diseases, acting as a main cause or as an aggravating factor. Its impact is actively studied in cardiovascular diseases representing major public health issues, like hypertension, but ASI could also play a role in aging and many more pathological processes including cancer.

TITLE: Les fonctions de l'innervation sympathique artérielle - Du développement à la pathologie. ABSTRACT: L'innervation sympathique artérielle (ISA) est un processus biologique complexe nécessitant un guidage fin des axones des neurones sympathiques par les artères. L'ISA est un élément clé de l'adaptation du système cardiovasculaire aux différentes contraintes (exposition au froid, exercice, etc.) : elle contrôle le diamètre des artères de résistance, donc le flux sanguin parvenant aux organes et la pression artérielle systémique via la modulation du tonus artériel. Son importance lors du vieillissement et dans de nombreux contextes pathologiques est de mieux en mieux reconnue et comprise. Son intégration à la prise en charge de nombreuses maladies (hypertension, cancer, etc.) permettrait d'en améliorer traitements et pronostic.

Blood stem cell-forming haemogenic endothelium in zebrafish derives from arterial endothelium.

Haematopoietic stem cells are generated from the haemogenic endothelium (HE) located in the floor of the dorsal aorta (DA). Despite being integral to arteries, it is controversial whether HE and arterial endothelium share a common lineage. Here, we present a transgenic zebrafish runx1 reporter line to isolate HE and aortic roof endothelium (ARE)s, excluding non-aortic endothelium. Transcriptomic analysis of these populations identifies Runx1-regulated genes and shows that HE initially expresses arterial markers at similar levels to ARE. Furthermore, runx1 expression depends on prior arterial programming by the Notch ligand dll4. Runx1-/- mutants fail to downregulate arterial genes in the HE, which remains integrated within the DA, suggesting that Runx1 represses the pre-existing arterial programme in HE to allow progression towards the haematopoietic fate. These findings strongly suggest that, in zebrafish, aortic endothelium is a precursor to HE, with potential implications for pluripotent stem cell differentiation protocols for the generation of transplantable HSCs.

Artery-vein specification in the zebrafish trunk is pre-patterned by heterogeneous Notch activity and balanced by flow-mediated fine-tuning.

How developing vascular networks acquire the right balance of arteries, veins and lymphatic vessels to efficiently supply and drain tissues is poorly understood. In zebrafish embryos, the robust and regular 50:50 global balance of intersegmental veins and arteries that form along the trunk prompts the intriguing question of how does the organism keep 'count'? Previous studies have suggested that the ultimate fate of an intersegmental vessel (ISV) is determined by the identity of the approaching secondary sprout emerging from the posterior cardinal vein. Here, we show that the formation of a balanced trunk vasculature involves an early heterogeneity in endothelial cell behaviour and Notch signalling activity in the seemingly identical primary ISVs that is independent of secondary sprouting and flow. We show that Notch signalling mediates the local patterning of ISVs, and an adaptive flow-mediated mechanism subsequently fine-tunes the global balance of arteries and veins along the trunk. We propose that this dual mechanism provides the adaptability required to establish a balanced network of arteries, veins and lymphatic vessels.

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a significant phenotype observed in individuals with 22q11 deletion syndrome and are caused by a microdeletion on chromosome 22q11. TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key gene, when mutated, for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9-deficient mice are born with complex cardiovascular malformations that affect the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared with Tbx1 heterozygous mice. Using a novel Pax9Cre allele, we demonstrated that the site of this Tbx1-Pax9 genetic interaction is the pharyngeal endoderm, therefore revealing that a Tbx1-Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for crucial tissue interactions during normal morphogenesis of the pharyngeal arch artery system.

Isl-1 positive pharyngeal mesenchyme subpopulation and its role in the separation and remodeling of the aortic sac in embryonic mouse heart.

BACKGROUND: Second heart field cells and neural crest cells have been reported to participate in the morphogenesis of the pharyngeal arch arteries (PAAs); however, how the PAAs grow out and are separated from the aortic sac into left and right sections is unknown. RESULTS: An Isl-1 positive pharyngeal mesenchyme protrusion in the aortic sac ventrally extends and fuses with the aortic sac wall to form a midsagittal septum that divides the aortic sac. The aortic sac division separates the left and right PAAs to form independent arteries. The midsagittal septum dividing the aortic sac has a different expression pattern from the aortic-pulmonary (AP) septum in which Isl-1 positive cells are absent. At 11 days post-conception (dpc) in a mouse embryo, the Isl-1 positive mesenchyme protrusion appears as a heart-shaped structure, in which subpopulations with Isl-1+ Tbx3+ and Isl-1+ Nkx2.5+ cells are included. CONCLUSIONS: The aortic sac is a dynamic structure that is continuously divided during the migration from the pharyngeal mesenchyme to the pericardial cavity. The separation of the aortic sac is not complete until the AP septum divides the aortic sac into the ascending aorta and pulmonary trunk. Moreover, the midsagittal septum and the AP septum are distinct structures.

Veins and Arteries Build Hierarchical Branching Patterns Differently: Bottom-Up versus Top-Down.

A tree-like hierarchical branching structure is present in many biological systems, such as the kidney, lung, mammary gland, and blood vessels. Most of these organs form through branching morphogenesis, where outward growth results in smaller and smaller branches. However, the blood vasculature is unique in that it exists as two trees (arterial and venous) connected at their tips. Obtaining this organization might therefore require unique developmental mechanisms. As reviewed here, recent data indicate that arterial trees often form in reverse order. Accordingly, initial arterial endothelial cell differentiation occurs outside of arterial vessels. These pre-artery cells then build trees by following a migratory path from smaller into larger arteries, a process guided by the forces imparted by blood flow. Thus, in comparison to other branched organs, arteries can obtain their structure through inward growth and coalescence. Here, new information on the underlying mechanisms is discussed, and how defects can lead to pathologies, such as hypoplastic arteries and arteriovenous malformations.

Peri-arterial specification of vascular mural cells from naïve mesenchyme requires Notch signaling.

Mural cells (MCs) are essential for blood vessel stability and function; however, the mechanisms that regulate MC development remain incompletely understood, in particular those involved in MC specification. Here, we investigated the first steps of MC formation in zebrafish using transgenic reporters. Using pdgfrb and abcc9 reporters, we show that the onset of expression of abcc9, a pericyte marker in adult mice and zebrafish, occurs almost coincidentally with an increment in pdgfrb expression in peri-arterial mesenchymal cells, suggesting that these transcriptional changes mark the specification of MC lineage cells from naïve pdgfrblow mesenchymal cells. The emergence of peri-arterial pdgfrbhigh MCs required Notch signaling. We found that pdgfrb-positive cells express notch2 in addition to notch3, and although depletion of notch2 or notch3 failed to block MC emergence, embryos depleted of both notch2 and notch3 lost mesoderm- as well as neural crest-derived pdgfrbhigh MCs. Using reporters that read out Notch signaling and Notch2 receptor cleavage, we show that Notch activation in the mesenchyme precedes specification into pdgfrbhigh MCs. Taken together, these results show that Notch signaling is necessary for peri-arterial MC specification.

Fetal dynamic phase-contrast MR angiography using ultrasound gating and comparison with Doppler ultrasound measurements.

OBJECTIVES: To investigate the feasibility of fetal phase-contrast (PC)-MR angiography of the descending aorta (AoD) using an MR-compatible Doppler ultrasound sensor (DUS) for fetal cardiac gating and to compare velocimetry with Doppler ultrasound measurements. METHODS: In this prospective study, 2D PC-MR angiography was performed in 12 human fetuses (mean gestational age 32.8 weeks) using an MR-compatible DUS for gating of the fetal heart at 1.5 T. Peak flow velocities in the fetal AoD were compared with Doppler ultrasound measurements performed on the same day. Reproducibility of PC-MR measurements was tested by repeated PC-MR in five fetuses. RESULTS: Dynamic PC-MR angiography in the AoD was successfully performed in all fetuses using the DUS, with an average fetal heart rate of 140 bpm (range 129-163). Time-velocity curves revealed typical arterial blood flow patterns. PC-MR mean flow velocity and mean flux were 21.2 cm/s (range 8.6-36.8) and 8.4 ml/s (range 3.2-14.6), respectively. A positive association between PC-MR mean flux and stroke volume with gestational age was obtained (r = 0.66, p = 0.02 and r = 0.63, p = 0.03). PC-MR and Doppler ultrasound peak velocities revealed a highly significant correlation (r = 0.8, p < 0.002). Peak velocities were lower for PC-MR with 69.1 cm/s (range 39-125) compared with 96.7 cm/s (range 60-142) for Doppler ultrasound (p < 0.001). Reproducibility of PC-MR was high (p > 0.05). CONCLUSION: The MR-compatible DUS for fetal cardiac gating allows for PC-MR angiography in the fetal AoD. Comparison with Doppler ultrasound revealed a highly significant correlation of peak velocities with underestimation of PC-MR velocities. This new technique for direct fetal cardiac gating indicates the potential of PC-MR angiography for assessing fetal hemodynamics. KEY POINTS: • The developed MR-compatible Doppler ultrasound sensor allows direct fetal cardiac gating and can be used for prenatal dynamic cardiovascular MRI. • The MR-compatible Doppler ultrasound sensor was successfully applied to perform intrauterine phase-contrast MR angiography of the fetal aorta, which revealed a highly significant correlation with Doppler ultrasound measurements. • As fetal flow hemodynamics is an important parameter in the diagnosis and management of fetal pathologies, fetal phase-contrast MR angiography may offer an alternative imaging method in addition to Doppler ultrasound and develop as a second line tool in the evaluation of fetal flow hemodynamics.

Reducing lung liquid volume increases biventricular outputs and systemic arterial blood flows despite decreased cardiac filling pressures in fetal lambs.

As prior work has shown that reducing lung liquid volume 1) increases pulmonary arterial (PA) blood flow, 2) augments right ventricular (RV) output/power, and 3) decreases left atrial (LA) pressure, we tested the hypothesis that this perturbation has global cardiovascular effects. Ten anesthetized, open-chest fetal lambs (128 ± 2 days gestation, full term = 147 days) were acutely instrumented with 1) LA and right atrial (RA) catheters, 2) aortic and pulmonary trunk catheters, 3) brachiocephalic trunk, aortic isthmus, ductal, and left PA flow probes to obtain left ventricular (LV) and RV outputs and hydraulic power and flow in the descending thoracic aorta, and 4) an endotracheal tube to remove lung liquid. A 17 ± 7 ml/kg reduction of lung liquid volume 1) decreased LA and RA pressures similarly (1.5-1.6 mmHg, P < 0.001), 2) augmented LV and RV outputs (21-24%, P < 0.001) and total power (27-28%, P < 0.005), 3) increased systolic flows in the brachiocephalic trunk (18%, P < 0.001), aortic isthmus (29%, P < 0.005), ductus (12%, P < 0.005), and descending thoracic aorta (16%, P < 0.001), 4) increased mean PA flow via a higher systolic inflow (37%, P < 0.001) and lower diastolic backflow (-16%, P < 0.05), and 5) did not change systemic vascular conductance or arterial compliance but increased both pulmonary vascular conductance and arterial compliance (1.8-fold, P < 0.001). These data suggest that hemodynamic effects of lung liquid volume reduction are not confined to the lungs but extend to all cardiac chambers via rises in LV and RV outputs and power, despite falls in cardiac filling pressures, as well as the systemic circulation, via downstream increases in systolic flows of major central arteries.

Arterial identity of hemogenic endothelium: a key to unlock definitive hematopoietic commitment in human pluripotent stem cell cultures.

Human pluripotent stem cells (hPSCs) have been suggested as a potential source for the de novo production of blood cells for transfusion, immunotherapies, and transplantation. However, even with advanced hematopoietic differentiation methods, the primitive and myeloid-restricted waves of hematopoiesis dominate in hPSC differentiation cultures, whereas cell surface markers to distinguish these waves of hematopoiesis from lympho-myeloid hematopoiesis remain unknown. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelium (HE) lining arteries, but not veins. This observation led to a long-standing hypothesis that arterial specification is an essential prerequisite to initiate the HSC program. It has also been established that lymphoid potential in the yolk sac and extraembryonic vasculature is mostly confined to arteries, whereas myeloid-restricted hematopoiesis is not specific to arterial vessels. Here, we review how the link between arterialization and the subsequent definitive multilineage hematopoietic program can be exploited to identify HE enriched in lymphoid progenitors and aid in in vitro approaches to enhance the production of lymphoid cells and potentially HSCs from hPSCs. We also discuss alternative models of hematopoietic specification at arterial sites and recent advances in our understanding of hematopoietic development and the production of engraftable hematopoietic cells from hPSCs.