Endothelial–Mesenchymal Interactions In Vitro Reveal Molecular Mechanisms of Smooth Muscle/Pericyte Differentiation

Ding, Rubai; Darland, Diane C.; Parmacek, Michael S.; D’Amore, Patricia A.

doi:10.1089/1547328042417336

Cited by 25 publications

(31 citation statements)

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“…As shown in Figure 6B–C, macrophages that had been “educated” by CM from PGC-α-expressing myotubes dramatically increased their ability to stimulate adjacent endothelial cells to migrate. Similar experiments with the differentiated 10 T1/2 model of pericytes 32, 33 (Figure 6D–E) and smooth muscle cells (Figure 6F–G) yielded similarly strong 2- to 3-fold increases in cell migration. These results thus indicate that PGC-1α expression in myotubes has a strong, indirect, effect on numerous vascular cells, via activation of macrophages.…”

Section: Resultssupporting

confidence: 75%

PGC-1α Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle

Rowe

Raghuram

Jang

et al. 2014

Circulation Research

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Rationale Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and Peripheral Artery Disease (PAD), but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and diabetic patients. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. PGC-1α, a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle. Objective To test if, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle. Methods and Results We show here that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types, and leads to patent, non-leaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of VEGF alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 (SPP1), and the recruitment of macrophages. SPP1 stimulates macrophages to secrete monocyte chemoattractant protein-1 (MCP-1), which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in SPP1 −/− mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hind-limb ischemia model of PAD. Conclusions PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.

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Section: Resultssupporting

confidence: 75%

PGC-1α Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle

Rowe

Raghuram

Jang

et al. 2014

Circulation Research

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“…During embryonic blood vessel formation, endothelial cells interact with surrounding mesenchymal cells and induce VSMC/pericyte differentiation [27]. Given that endothelial-mesenchymal cell interactions appeared impaired in the absence of PRKCD and PRKCE (Fig.…”

Section: Resultsmentioning

confidence: 99%

Redundant Role of Protein Kinase C Delta and Epsilon during Mouse Embryonic Development

Carracedo

Sacher²,

Brandes³

et al. 2014

PLoS ONE

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Protein Kinase C delta and epsilon are mediators of important cellular events, such as cell proliferation, migration or apoptosis. The formation of blood vessels, i.e., vasculo- and angiogenesis, is a process where these isoforms have also been shown to participate. However, mice deficient in either Protein Kinase C delta or epsilon are viable and therefore their individual contribution to the formation of the vasculature appeared so far dispensable. In this study, we show that double null mutation of Protein Kinase C delta and epsilon causes embryonic lethality at approximately E9.5. At this stage, whole mount staining of the endothelial marker CD31 in double null embryos revealed defective blood vessel formation. Moreover, culture of double deficient mouse allantois showed impaired endothelial cell organization, and analyses of double deficient embryo sections showed dilated vessels, decreased endothelial-specific adherent junctions, and decreased contact of endothelial cells with mural cells. Protein kinase C delta and epsilon also appeared essential for vascular smooth muscle cell differentiation, since α-smooth muscle actin, a classical marker for vascular smooth muscle cells, was almost undetectable in double deficient embryonic aorta at E9.5. Subsequent qPCR analyses showed decreased VE-cadherin, Vegfr2, Cd31, Cdh2, Ets1, and Fli-1, among other angiogenesis related transcripts in double deficient embryos. Taken together, these data suggest for the first time an in vivo redundant role between members of the novel Protein Kinase C subfamily that allows for mutual compensation during mouse embryonic development, with vasculogenesis/angiogenesis as an obvious common function of these two Protein Kinase Cs. Protein Kinase C delta and epsilon might therefore be useful targets for inhibiting vasculo- and/or angiogenesis.

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“…Higher magnification Z-stack confocal images (of the squares in A) from top (i), middle (ii), and bottom (iii) show the outer localization of SMLCs and the inner lining EPCs. Scale bar is 100 μm type to reflect a more differentiated state [50,51]. SMLCs may stabilize CLSs in vitro by both cytokine interactions and physical arrangement, by wrapping the inner lining of EPCs, providing a supportive layer for the developing network [4,5,7,48,52,53].…”

Section: Discussionmentioning

confidence: 99%

Smooth-Muscle-Like Cells Derived from Human Embryonic Stem Cells Support and Augment Cord-Like Structures In Vitro

Hanjaya‐Putra

Zha

et al. 2010

Stem Cell Rev and Rep

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Engineering vascularized tissue is crucial for its successful implantation, survival, and integration with the host tissue. Vascular smooth muscle cells (v-SMCs) provide physical support to the vasculature and aid in maintaining endothelial viability. In this study, we show an efficient derivation of v-SMCs from human embryonic stem cells (hESCs), and demonstrate their functionality and ability to support the vasculature in vitro. Human ESCs were differentiated in monolayers and supplemented with platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-beta 1 (TGF-beta1). Human ESC-derived smooth-muscle-like cells (SMLCs) were found to highly express specific smooth muscle cell (SMC) markers--including alpha-smooth muscle actin, calponin, SM22, and smooth muscle myosin heavy chain--to produce and secrete fibronectin and collagen, and to contract in response to carbachol. In vitro tubulogenesis assays revealed that these hESC-derived SMLCs interacted with human endothelial progenitor cell (EPCs) to form longer and thicker cord-like structures in vitro. We have demonstrated a simple protocol for the efficient derivation of highly purified SMLCs from hESCs. These in vitro functional SMLCs interacted with EPCs to support and augment capillary-like structures (CLSs), demonstrating the potential of hESCs as a cell source for therapeutic vascular tissue engineering.

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Endothelial–Mesenchymal Interactions In Vitro Reveal Molecular Mechanisms of Smooth Muscle/Pericyte Differentiation

Cited by 25 publications

References 0 publications

PGC-1α Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle

PGC-1α Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle

Redundant Role of Protein Kinase C Delta and Epsilon during Mouse Embryonic Development

Smooth-Muscle-Like Cells Derived from Human Embryonic Stem Cells Support and Augment Cord-Like Structures In Vitro

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