Arterial Morphogenesis Research Articles

Exosomal miRNAs Differentiate Chronic Total Occlusion from Acute Myocardial Infarction.

Although coronary artery occlusion can have a negative effect on the myocardium, chronic total occlusion (CTO) exhibits different clinical features from those of acute myocardial infarction (AMI). In this study, we identify the differential associations of exosomal miRNAs with CTO and AMI. Exosomes were isolated from the plasma obtained from coronary arteries of patients undergoing percutaneous coronary intervention to treat CTO (n = 29) and AMI (n = 24), followed by small RNA sequencing, target gene predictions, and functional enrichment analyses. Promising miRNA markers were validated using real-time PCR in 35 CTO, 35 AMI, and 10 normal subjects. A total of 205 miRNAs were detected in all subjects, and 20 and 12 miRNAs were upregulated and downregulated in CTO compared to AMI patients, respectively (|fold change| > 4, FDR q < 0.05). The target genes of miRNAs that were higher in CTO patients were associated with "regulation of cell cycle phase transition", "cell growth", and "apoptosis". The target genes of miRNAs that were lower in CTO patients were enriched in terms such as "muscle cell differentiation", "response to oxygen levels", and "artery morphogenesis". On qRT-PCR analysis, the expression levels of miR-9-5p and miR-127-3p were significantly different between CTO and AMI patients. The miRNA expression levels accurately distinguished CTO from AMI patients with 79% specificity and 97% sensitivity. The miRNA contents of plasma exosomes were significantly different between CTO and AMI patients. The miRNAs may play important roles in CTO and AMI.

Buffering Mechanism in Aortic Arch Artery Formation and Congenital Heart Disease.

The resiliency of embryonic development to genetic and environmental perturbations has been long appreciated; however, little is known about the mechanisms underlying the robustness of developmental processes. Aberrations resulting in neonatal lethality are exemplified by congenital heart disease arising from defective morphogenesis of pharyngeal arch arteries (PAAs) and their derivatives. Mouse genetics, lineage tracing, confocal microscopy, and quantitative image analyses were used to investigate mechanisms of PAA formation and repair. The second heart field (SHF) gives rise to the PAA endothelium. Here, we show that the number of SHF-derived endothelial cells (ECs) is regulated by VEGFR2 (vascular endothelial growth factor receptor 2) and Tbx1. Remarkably, when the SHF-derived EC number is decreased, PAA development can be rescued by the compensatory endothelium. Blocking such compensatory response leads to embryonic demise. To determine the source of compensating ECs and mechanisms regulating their recruitment, we investigated 3-dimensional EC connectivity, EC fate, and gene expression. Our studies demonstrate that the expression of VEGFR2 by the SHF is required for the differentiation of SHF-derived cells into PAA ECs. The deletion of 1 VEGFR2 allele (VEGFR2SHF-HET) reduces SHF contribution to the PAA endothelium, while the deletion of both alleles (VEGFR2SHF-KO) abolishes it. The decrease in SHF-derived ECs in VEGFR2SHF-HET and VEGFR2SHF-KO embryos is complemented by the recruitment of ECs from the nearby veins. Compensatory ECs contribute to PAA derivatives, giving rise to the endothelium of the aortic arch and the ductus in VEGFR2SHF-KO mutants. Blocking the compensatory response in VEGFR2SHF-KO mutants results in embryonic lethality shortly after mid-gestation. The compensatory ECs are absent in Tbx1+/- embryos, a model for 22q11 deletion syndrome, leading to unpredictable arch artery morphogenesis and congenital heart disease. Tbx1 regulates the recruitment of the compensatory endothelium in an SHF-non-cell-autonomous manner. Our studies uncover a novel buffering mechanism underlying the resiliency of PAA development and remodeling.

Renal artery morphogenesis rediscovered from 3D reconstructions of human embryos

Renal artery morphogenesis rediscovered from 3D reconstructions of human embryos

BMPing up endocardial angiogenesis to generate coronary vessels.

Understanding how coronary vessels develop is important for designing better strategies to repair ischemic hearts. In this issue of Developmental Cell, D'Amato etal. report that BMP2 and CXCL12/CXCR4 act sequentially on endocardial cells to drive coronary angiogenesis and artery morphogenesis.

Endocardium-to-coronary artery differentiation during heart development and regeneration involves sequential roles of Bmp2 and Cxcl12/Cxcr4.

Endocardial cells lining the heart lumen are coronary vessel progenitors during embryogenesis. Re-igniting this developmental process in adults could regenerate blood vessels lost during cardiac injury, but this requires additional knowledge of molecular mechanisms. Here, we use mouse genetics and scRNA-seq to identify regulators of endocardial angiogenesis and precisely assess the role of CXCL12/CXCR4 signaling. Time-specific lineage tracing demonstrated that endocardial cells differentiated into coronary endothelial cells primarily at mid-gestation. A new mouse line reporting CXCR4 activity-along with cell-specific gene deletions-demonstrated it was specifically required for artery morphogenesis rather than angiogenesis. Integrating scRNA-seq data of endocardial-derived coronary vessels from mid- and late-gestation identified a Bmp2-expressing transitioning population specific to mid-gestation. Bmp2 stimulated endocardial angiogenesis invitro and in injured neonatal mouse hearts. Our data demonstrate how understanding the molecular mechanisms underlying endocardial angiogenesis can identify new potential therapeutic targets promoting revascularization of the injured heart.

Melanocytes determine angiogenesis gene expression across human tissues.

Several angiogenesis-dependent diseases, including age-related macular degeneration and infantile hemangioma, display differential prevalence among Black, as compared to White individuals. Although socioeconomic status and genetic architecture have been suggested as explaining these differences, we have recently shown that pigment production per se might be involved. For example, we have shown that the extracellular protein fibromodulin is a pro-angiogenic factor highly secreted by melanocytes in White but not Black individuals. Still, additional pigment-dependent angiogenic factors and their molecular mechanisms remain to be identified. Understanding the contribution of pigmentation to angiogenesis in health and disease is essential for precision medicine of angiogenesis-dependent diseases with racial disparity. Toward that goal, we compared the transcriptomes of Black and White individuals in three tissues with angiogenic activity, namely artery, whole blood, and skin. We identified several differentially expressed angiogenesis pathways, including artery morphogenesis, regulation of endothelial cell chemotaxis, and cellular response to vascular endothelial growth factor stimulus. We then demonstrated that the expression of key genes in these pathways is directly modulated by the degree of pigmentation. We further identified the precise pigment production pathway controlling the expression of these genes, namely melanocortin 1 receptor (MC1R) signaling. These results demonstrate pigment-mediated regulation of angiogenesis-related pathways and their driver genes across human tissues.

Integrating Matrix Signals During Arch Artery Morphogenesis

Integrating Matrix Signals During Arch Artery Morphogenesis

Cell-Extracellular Matrix Interactions Play Multiple Essential Roles in Aortic Arch Development.

Defects in the morphogenesis of the fourth pharyngeal arch arteries (PAAs) give rise to lethal birth defects. Understanding genes and mechanisms regulating PAA formation will provide important insights into the etiology and treatments for congenital heart disease. Cell-ECM (extracellular matrix) interactions play essential roles in the morphogenesis of PAAs and their derivatives, the aortic arch artery and its major branches; however, their specific functions are not well-understood. Previously, we demonstrated that integrin α5β1 and Fn1 (fibronectin) expressed in the Isl1 lineages regulate PAA formation. The objective of the current studies was to investigate cellular mechanisms by which integrin α5β1 and Fn1 regulate aortic arch artery morphogenesis. Using temporal lineage tracing, whole-mount confocal imaging, and quantitative analysis of the second heart field (SHF) and endothelial cell (EC) dynamics, we show that the majority of PAA EC progenitors arise by E7.5 in the SHF and contribute to pharyngeal arch endothelium between E7.5 and E9.5. Consequently, SHF-derived ECs in the pharyngeal arches form a plexus of small blood vessels, which remodels into the PAAs by 35 somites. The remodeling of the vascular plexus is orchestrated by signals dependent on the pharyngeal ECM microenvironment, extrinsic to the endothelium. Conditional ablation of integrin α5β1 or Fn1 in the Isl1 lineages showed that signaling by the ECM regulates aortic arch artery morphogenesis at multiple steps: (1) accumulation of SHF-derived ECs in the pharyngeal arches, (2) remodeling of the EC plexus in the fourth arches into the PAAs, and (3) differentiation of neural crest-derived cells adjacent to the PAA endothelium into vascular smooth muscle cells. PAA formation is a multistep process entailing dynamic contribution of SHF-derived ECs to pharyngeal arches, the remodeling of endothelial plexus into the PAAs, and the remodeling of the PAAs into the aortic arch artery and its major branches. Cell-ECM interactions regulated by integrin α5β1 and Fn1 play essential roles at each of these developmental stages.

Pax9 and Gbx2 Interact in the Pharyngeal Endoderm to Control Cardiovascular Development.

The correct formation of the aortic arch arteries depends on a coordinated and regulated gene expression profile within the tissues of the pharyngeal arches. Perturbation of the gene regulatory networks in these tissues results in congenital heart defects affecting the arch arteries and the outflow tract of the heart. Aberrant development of these structures leads to interruption of the aortic arch and double outlet right ventricle, abnormalities that are a leading cause of morbidity in 22q11 Deletion Syndrome (DS) patients. We have recently shown that Pax9 functionally interacts with the 22q11DS gene Tbx1 in the pharyngeal endoderm for 4th pharyngeal arch artery morphogenesis, with double heterozygous mice dying at birth with interrupted aortic arch. Mice lacking Pax9 die perinatally with complex cardiovascular defects and in this study we sought to validate further potential genetic interacting partners of Pax9, focussing on Gbx2 which is down-regulated in the pharyngeal endoderm of Pax9-null embryos. Here, we describe the Gbx2-null cardiovascular phenotype and demonstrate a genetic interaction between Gbx2 and Pax9 in the pharyngeal endoderm during cardiovascular development.

High Bifurcation of the Brachial Artery: An Embryological Overview.

The brachial artery is the main artery of the arm and constitutes the continuation of the axillary artery. It gives off two terminal branches, the radial and ulnar arteries. According to the literature, the brachial artery might present a deviation from the normal pattern in 20% of the cases. High bifurcation of the artery seems to be the most common variation and may result in a series of complications during surgery and interventional radiology. An embryological overview is necessary for a better understanding of this variant. The brachial artery is being developed during embryonic life by the main trunk of the axis artery. The superficial brachial artery is also an important stable fetal vessel for normal arterial morphogenesis of the upper limb.

Coronary arterial development is regulated by a Dll4-Jag1-EphrinB2 signaling cascade.

Coronaries are essential for myocardial growth and heart function. Notch is crucial for mouse embryonic angiogenesis, but its role in coronary development remains uncertain. We show Jag1, Dll4 and activated Notch1 receptor expression in sinus venosus (SV) endocardium. Endocardial Jag1 removal blocks SV capillary sprouting, while Dll4 inactivation stimulates excessive capillary growth, suggesting that ligand antagonism regulates coronary primary plexus formation. Later endothelial ligand removal, or forced expression of Dll4 or the glycosyltransferase Mfng, blocks coronary plexus remodeling, arterial differentiation, and perivascular cell maturation. Endocardial deletion of Efnb2 phenocopies the coronary arterial defects of Notch mutants. Angiogenic rescue experiments in ventricular explants, or in primary human endothelial cells, indicate that EphrinB2 is a critical effector of antagonistic Dll4 and Jag1 functions in arterial morphogenesis. Thus, coronary arterial precursors are specified in the SV prior to primary coronary plexus formation and subsequent arterial differentiation depends on a Dll4-Jag1-EphrinB2 signaling cascade.

PDGF signaling from pharyngeal pouches promotes arch artery morphogenesis

The great vessels of the heart originate from the pharyngeal arch arteries (PAAs). Anomalies of the PAAs often occur together with pharyngeal pouch malformations, but the reasons for this phenomenon are not fully understood. In the current study, we show that platelet-derived growth factor (PDGF) signaling derived from the pharyngeal pouches plays an important function in PAA vasculogenesis. During PAA development in zebrafish embryos, pdgfαa and pdgfαb are expressed in the developing pharyngeal pouches. Results from loss-of-function experiments revealed a critical role of these genes in PAA formation. We found that nitroreductase (NTR)-mediated pouch ablation distinctly decreased PDGF receptor tyrosine phosphorylation, yielding a severe loss of PAAs. Importantly, pouch-specific overexpression of pdgfαa in pdgfαa−/−; pdgfαb−/− mutants significantly relieved the PAA defects, which indicated a primary role of pharyngeal pouch-expressed PDGF ligands in signal activation and PAA morphogenesis. Our findings further showed that PDGF signaling was indispensable for the proliferation of PAA angioblasts. Together, these results established a role for PDGFαa- and PDGFαb-mediated tissue-tissue interaction during PAA development.

Selective downregulation of distinct circRNAs in the tissues and plasma of patients with primary hepatic carcinoma.

Multiple studies have indicated that circular RNAs (circRNAs) are closely associated with malignant tumor development and metastasis. However, the significance of circRNAs in primary hepatic carcinoma (PHC), particularly in the plasma, remains largely undetermined. In the current study, circRNA expression profiles in three pairs of tumor and adjacent normal samples from patients with PHC, were examined using circRNA chip screening. A total of 80 circRNAs were upregulated, while 75 circRNAs were downregulated in PHC tissues, relative to para-tumor tissues (fold change, ≥1.5). A total of two upregulated circRNAs and three downregulated circRNAs were selected as candidates for further validation of their differential expression. This was performed using reverse transcription-quantitative PCR with 11 pairs of PHC tissues and para-tumor tissues. The results indicated that hsa_circ_0003056 exhibited reduced expression in PHC tissues. Moreover, hsa_circ_0003056 and hsa_circ_0067127 were quantified in the plasma samples of 35 PHC patients and 32 healthy donors. The results revealed that hsa_circ_0067127 was significantly downregulated in the patients' plasma. Finally, a competing endogenous RNA network was constructed, which consisted of one circRNA (hsa_circ_0003056 or has_circ_0067127), five miRNAs and miRNA-targeted genes (mRNAs). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that differentially expressed (DE) genes were significantly enriched in the pathway associated with ‘regulation of the pluripotency of stem cells’ for hsa_circ_0003056, and ‘ubiquitin-mediated proteolysis’ and ‘prostate cancer’ for hsa_circ_0067127. Gene ontology analysis revealed that DE genes were primarily associated with the ‘modulation of kinase activity’ and ‘intracellular and transmembrane-ephrin receptor activity’ for hsa_circ_0003056, ‘artery morphogenesis activity’, ‘HOPS complex and transferase activity’ and in ‘transferring acyl groups’ for hsa_circ_0067127. This approach indicated that hsa_circ_0003056 in PHC tissue, and hsa_circ_0067127 in PHC plasma, are downregulated and may be implicated in the tumorigenesis of PHC.

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

ABSTRACTDevelopmental 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.

Laminin-dystroglycan signaling regulates retinal arteriogenesis.

Proper arteriovenous morphogenesis is crucial for maintaining normal tissue perfusion. However, our understanding of how arterial morphogenesis is regulated in the CNS is incomplete. In this study, we asked whether vascular basement membrane (BM) laminins, specifically the γ3-containing isoforms, regulate retinal arterial morphogenesis. We provide evidence that Laminin-γ3 is deposited at both arterial and venous BMs during arteriogenesis. Vascular BM Laminin-γ3 bound dystroglycan (DG), a laminin receptor preferentially expressed by arterial endothelial cells (ECs) during arteriogenesis. Blockade of laminin-DG binding in vitro led to decreased Delta-like ligand (DLL)-4 expression in ECs. Moreover, genetic deletion of the Laminin-γ3- and EC-specific deletion of DG led to similar defects in retinal arteriogenesis, including reduced Dll4 expression, hyperbranching and reduced smooth muscle coverage. These results implicate a newly identified Laminin-γ3-DG signaling cascade that regulates arterial Dll4/Notch signaling to specify and stabilize retinal arteries.-Biswas, S., Watters, J., Bachay, G., Varshney, S., Hunter, D. D., Hu, H., Brunken, W. J. Laminin-dystroglycan signaling regulates retinal arteriogenesis.

Extracellular Determinants of Arterial Morphogenesis, Growth, and Homeostasis.

The extracellular matrix (ECM) is a highly heterogeneous mixture of macromolecules capable of self-assembling into tissue-specific suprastructures that constitute the architectural elements supporting organ function. Contrary to the traditional view of being a static scaffold that supports tissue integrity along with cell adhesion and migration, the ECM is an inherently dynamic system that specifies cellular function and defines the limits and patterns of tissue organization. Throughout evolution, the composition and organization of the ECM have changed to accommodate basic and new tissue functions, both in terms of providing structural support and integrating multivalent signals to cells. In this review, we will highlight some of these bidirectional cell-matrix interactions that guide the development of a mechanically compliant vascular system. Specifically, we will focus on studies that have investigated how ECM composition and physical properties influence cell fate decisions associated with vascular tissue development and homeostasis and implicitly, vascular disease.

Planar cell polarity genes frizzled4 and frizzled6 exert patterning influence on arterial vessel morphogenesis.

Quantitative analysis of the vascular network anatomy is critical for the understanding of the vasculature structure and function. In this study, we have combined microcomputed tomography (microCT) and computational analysis to provide quantitative three-dimensional geometrical and topological characterization of the normal kidney vasculature, and to investigate how 2 core genes of the Wnt/planar cell polarity, Frizzled4 and Frizzled6, affect vascular network morphogenesis. Experiments were performed on frizzled4 (Fzd4-/-) and frizzled6 (Fzd6-/-) deleted mice and littermate controls (WT) perfused with a contrast medium after euthanasia and exsanguination. The kidneys were scanned with a high-resolution (16 μm) microCT imaging system, followed by 3D reconstruction of the arterial vasculature. Computational treatment includes decomposition of 3D networks based on Diameter-Defined Strahler Order (DDSO). We have calculated quantitative (i) Global scale parameters, such as the volume of the vasculature and its fractal dimension (ii) Structural parameters depending on the DDSO hierarchical levels such as hierarchical ordering, diameter, length and branching angles of the vessel segments, and (iii) Functional parameters such as estimated resistance to blood flow alongside the vascular tree and average density of terminal arterioles. In normal kidneys, fractal dimension was 2.07±0.11 (n = 7), and was significantly lower in Fzd4-/- (1.71±0.04; n = 4), and Fzd6-/- (1.54±0.09; n = 3) kidneys. The DDSO number was 5 in WT and Fzd4-/-, and only 4 in Fzd6-/-. Scaling characteristics such as diameter and length of vessel segments were altered in mutants, whereas bifurcation angles were not different from WT. Fzd4 and Fzd6 deletion increased vessel resistance, calculated using the Hagen-Poiseuille equation, for each DDSO, and decreased the density and the homogeneity of the distal vessel segments. Our results show that our methodology is suitable for 3D quantitative characterization of vascular networks, and that Fzd4 and Fzd6 genes have a deep patterning effect on arterial vessel morphogenesis that may determine its functional efficiency.

Abstract 552: End Stage Human Aneurysm Disease in Different Arterial Positions is Similar, Aneurysm Induction in Mouse Models is Not

Introduction: Aneurysm disease occurs throughout the arterial tree, abdominal aortic aneurysm (AAA) and popliteal artery aneurysm (PAA) being the most frequent ones. The pathology is best examined, yet little understood, for AAA. Aneurysm disease has distinct features like angiogenesis and phenotype switch of vascular smooth muscle cells (VSMC). However, little is known about these characteristics in other than AAA. Material and Methods: From a surgical biobank we compared 42 AAA, 15 PAA, 3 ascending aortic, 5 iliac, 3 femoral, 2 brachial, 1 visceral and 1 carotid artery aneurysm on morphologic, protein and mRNA-expression levels. Two multi-stage mouse models of aneurysm disease were applied to test response to aneurysm induction at different arterial locations. Results: AAAs show a varying histomorphologic appearance, not seen in PAA, which, in turn, has a high proliferation rate in the aneurysm sac, making other than surgical interventions appealing. All entities show VSMC phenotype switch, angiogenesis, matrix remodeling and T-cell/macrophage inflammation. AAA and PAA have similar alterations in TGFß-signaling. To further investigate these conditions in mouse models, we applied the PPE procedure to a juxtarenal aorta and the EPA model to a thoracic, abdominal and femoral location. Conclusion: Despite different arterial morphogenesis, advanced aneurysm disease from human intraoperative specimen shows similar characteristics of end-stage disease.

Neural crest cell-autonomous roles of fibronectin in cardiovascular development

The chemical and mechanical properties of extracellular matrices (ECMs) modulate diverse aspects of cellular fates; however, how regional heterogeneity in ECM composition regulates developmental programs is not well understood. We discovered that fibronectin 1 (Fn1) is expressed in strikingly non-uniform patterns during mouse development, suggesting that regionalized synthesis of the ECM plays cell-specific regulatory roles during embryogenesis. To test this hypothesis, we ablated Fn1 in the neural crest (NC), a population of multi-potent progenitors expressing high levels of Fn1. We found that Fn1 synthesized by the NC mediated morphogenesis of the aortic arch artery and differentiation of NC cells into vascular smooth muscle cells (VSMCs) by regulating Notch signaling. We show that NC Fn1 signals in an NC cell-autonomous manner through integrin α5β1 expressed by the NC, leading to activation of Notch and differentiation of VSMCs. Our data demonstrate an essential role of the localized synthesis of Fn1 in cardiovascular development and spatial regulation of Notch signaling.

In This Issue

HomeCirculation ResearchVol. 113, No. 9In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Originally published12 Oct 2013https://doi.org/10.1161/01.res.0000435801.75994.a9Circulation Research. 2013;113:1033Raet1e, a New Atherosclerosis Modifier Gene (p 1054)Download figureDownload PowerPointRodriguez et al identify a new atherosclerosis modifier gene in mice.Atherosclerosis is a complex disease involving both environmental factors—for example, diet—and genes. Genetic loci that confer increased or decreased susceptibility to atherosclerosis have been identified in mice and man, but pinpointing the causative sequence changes at these loci is not easy. Out of the 44 or so modifier loci identified in mice, for example, the modifier sequences have been identified at just a handful. Now Rodriguez and colleagues add another locus to that list—Ath11. This locus, which associates with more severe atherosclerosis, maps to a particular stretch of mouse chromosome 10. The team identified five possible candidate genes in the region and analyzed their expression in atherosclerosis-prone mice that were either homozygous or heterozygous for the Ath11 modifier—and that had more or less severe atherosclerosis as a result. One gene, Raet1e, exhibited lower expression levels in the homozygotes. And reinstating high expression of Raet1e, by means of a transgene, reduced the severity of atherosclerosis. The team went on to identify the sequence change in the promoter of Raet1e responsible for the reduced expression. It is not clear why low levels of Raet1e worsen atherosclerosis, but the protein is known to interact with immune cells suggesting that an aberrant immune response may be to blame.Quaking and VSMC Phenotype (p 1065)Download figureDownload PowerPointBlocking an RNA-binding factor called Quaking prevents vascular smooth muscle cells from over- proliferating, report van der Veer et al.Quaking (QKI) is an RNA binding protein that regulates splicing, export and stability of messenger RNAs, and has been shown to be important for vascular development in the embryo. Van der Veer and colleagues investigated whether QKI might also have a role in the adult vasculature. They found that in healthy human vessels, smooth muscle cells (VSMCs) expressed almost undetectable levels of QKI, but that in restenotic vessels—where the VSMCs dedifferentiate and proliferate rapidly—the cells showed a dramatic increase in QKI expression. In concordance, mice that expressed a reduced amount of QKI exhibited less severe restenosis after vessel injury. VSMCs derived from these mice also displayed reduced proliferation, migration and extracellular matrix production—indicators of restenosis. The team went on to show that QKI interacted with the pre-mRNA of myocardin—an important promoter of VSMC maturation—and promoted the excision of one of myocardin’s exons. This splicing event generated a version of myocardin that increased VSMC proliferation. The authors therefore suggest that interfering with QKI activity could be a therapeutic path toward ameliorating pathogenic restenosis after vessel injury.Cellular Basis of Arteriogenesis (p 1076)Download figureDownload PowerPointEndothelial cells are principle regulators of arteriogenesis, say Moraes et al.Recent research into arteriogenesis—the development of arteries and smaller arterioles—indicates that an intracellular signaling protein called synectin is involved. For example, mice and zebrafish that lack synectin exhibit impaired arterial morphogenesis. Their vessels are smaller sized with reduced diameters as well as reduced numbers of branches. Moraes et al were interested in which cell type might be responsible for these synectin-associated arterial defects. They generated mice that specifically lacked synectin in each of the two major artery cell types: vascular smooth muscle cells (VSMCs) and endothelial cells. They found that mice lacking synectin in endothelial cells but not those lacking synectin in their VSMCs exhibited virtually the same developmental arterial defects as the whole-mouse synectin deletion. Furthermore, when the researchers induced ischemia in the hind-limbs of adult mice, those lacking synectin in their endothelial cells had impaired recovery of blood flow while those lacking synectin in their VSMCs did not. The work provides a greater understanding of the molecular and cellular mechanisms behind artery formation, which will aid in the design of future therapies for ischemic vascular diseases, say the authors. Previous Back to top Next FiguresReferencesRelatedDetails October 12, 2013Vol 113, Issue 9 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/01.res.0000435801.75994.a9 Originally publishedOctober 12, 2013 PDF download Advertisement