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1. Evolutionarily conserved sequence motif analysis guides development of chemically defined hydrogels for therapeutic vascularization

   https://doi.org/10.1126/sciadv.aaz5894  

   Jia, Jia ; Jeon, Eun Je ; Li, Mei ; Richards, Dylan J. ; Lee, Soojin ; Jung, Youngmee ; Barrs, Ryan W. ; Coyle, Robert ; Li, Xiaoyang ; Chou, James C. ; et al ( July 2020 , Science Advances)

   null (Ed.)

   Biologically active ligands (e.g., RGDS from fibronectin) play critical roles in the development of chemically defined biomaterials. However, recent decades have shown only limited progress in discovering novel extracellular matrix–protein–derived ligands for translational applications. Through motif analysis of evolutionarily conserved RGD-containing regions in laminin (LM) and peptide-functionalized hydrogel microarray screening, we identified a peptide (a1) that showed superior supports for endothelial cell (EC) functions. Mechanistic studies attributed the results to the capacity of a1 engaging both LM- and Fn-binding integrins. RNA sequencing of ECs in a1-functionalized hydrogels showed ~60% similarities with Matrigel in “vasculature development” gene ontology terms. Vasculogenesis assays revealed the capacity of a1-formulated hydrogels to improve EC network formation. Injectable alginates functionalized with a1 and MMPQK (a vascular endothelial growth factor–mimetic peptide with a matrix metalloproteinase–degradable linker) increased blood perfusion and functional recovery over decellularized extracellular matrix and (RGDS + MMPQK)–functionalized hydrogels in an ischemic hindlimb model, illustrating the power of this approach. 

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2. Elastin‐like protein hydrogels with controllable stress relaxation rate and stiffness modulate endothelial cell function

   https://doi.org/10.1002/jbm.a.37520  

   Shayan, Mahdis ; Huang, Michelle S. ; Navarro, Renato ; Chiang, Gladys ; Hu, Caroline ; Oropeza, Beu P. ; Johansson, Patrik K. ; Suhar, Riley A. ; Foster, Abbygail A. ; LeSavage, Bauer L. ; et al ( March 2023 , Journal of Biomedical Materials Research Part A)

   Mechanical cues from the extracellular matrix (ECM) regulate vascular endothelial cell (EC) morphology and function. Since naturally derived ECMs are viscoelastic, cells respond to viscoelastic matrices that exhibit stress relaxation, in which a cell‐applied force results in matrix remodeling. To decouple the effects of stress relaxation rate from substrate stiffness on EC behavior, we engineered elastin‐like protein (ELP) hydrogels in which dynamic covalent chemistry (DCC) was used to crosslink hydrazine‐modified ELP (ELP‐HYD) and aldehyde/benzaldehyde‐modified polyethylene glycol (PEG‐ALD/PEG‐BZA). The reversible DCC crosslinks in ELP‐PEG hydrogels create a matrix with independently tunable stiffness and stress relaxation rate. By formulating fast‐relaxing or slow‐relaxing hydrogels with a range of stiffness (500–3300 Pa), we examined the effect of these mechanical properties on EC spreading, proliferation, vascular sprouting, and vascularization. The results show that both stress relaxation rate and stiffness modulate endothelial spreading on two‐dimensional substrates, on which ECs exhibited greater cell spreading on fast‐relaxing hydrogels up through 3 days, compared with slow‐relaxing hydrogels at the same stiffness. In three‐dimensional hydrogels encapsulating ECs and fibroblasts in coculture, the fast‐relaxing, low‐stiffness hydrogels produced the widest vascular sprouts, a measure of vessel maturity. This finding was validated in a murine subcutaneous implantation model, in which the fast‐relaxing, low‐stiffness hydrogel produced significantly more vascularization compared with the slow‐relaxing, low‐stiffness hydrogel. Together, these results suggest that both stress relaxation rate and stiffness modulate endothelial behavior, and that the fast‐relaxing, low‐stiffness hydrogels supported the highest capillary density in vivo.

    

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3. The pericyte microenvironment during vascular development

   https://doi.org/10.1111/micc.12554  

   Payne, Laura B. ; Zhao, Huaning ; James, Carissa C. ; Darden, Jordan ; McGuire, David ; Taylor, Sarah ; Smyth, James W. ; Chappell, John C. ( May 2019 , Microcirculation)

   Vascular pericytes provide critical contributions to the formation and integrity of the blood vessel wall within the microcirculation. Pericytes maintain vascular stability and homeostasis by promoting endothelial cell junctions and depositing extracellular matrix (ECM) components within the vascular basement membrane, among other vital functions. As their importance in sustaining microvessel health within various tissues and organs continues to emerge, so does their role in a number of pathological conditions including cancer, diabetic retinopathy, and neurological disorders. Here, we review vascular pericyte contributions to the development and remodeling of the microcirculation, with a focus on the local microenvironment during these processes. We discuss observations of their earliest involvement in vascular development and essential cues for their recruitment to the remodeling endothelium. Pericyte involvement in the angiogenic sprouting context is also considered with specific attention to crosstalk with endothelial cells such as through signaling regulation and ECM deposition. We also address specific aspects of the collective cell migration and dynamic interactions between pericytes and endothelial cells during angiogenic sprouting. Lastly, we discuss pericyte contributions to mechanisms underlying the transition from active vessel remodeling to the maturation and quiescence phase of vascular development.

    

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4. Self-organizing behaviors of cardiovascular cells on synthetic nanofiber scaffolds

   https://doi.org/10.1063/5.0172423  

   Peters, Michael M. ; Brister, Jackson K. ; Tang, Edward M. ; Zhang, Felita W. ; Lucian, Veronica M. ; Trackey, Paul D. ; Bone, Zachary ; Zimmerman, John F. ; Jin, Qianru ; Burpo, F. John ; et al ( December 2023 , APL Bioengineering)

   In tissues and organs, the extracellular matrix (ECM) helps maintain inter- and intracellular architectures that sustain the structure–function relationships defining physiological homeostasis. Combining fiber scaffolds and cells to form engineered tissues is a means of replicating these relationships. Engineered tissues' fiber scaffolds are designed to mimic the topology and chemical composition of the ECM network. Here, we asked how cells found in the heart compare in their propensity to align their cytoskeleton and self-organize in response to topological cues in fibrous scaffolds. We studied cardiomyocytes, valvular interstitial cells, and vascular endothelial cells as they adapted their inter- and intracellular architectures to the extracellular space. We used focused rotary jet spinning to manufacture aligned fibrous scaffolds to mimic the length scale and three-dimensional (3D) nature of the native ECM in the muscular, valvular, and vascular tissues of the heart. The representative cardiovascular cell types were seeded onto fiber scaffolds and infiltrated the fibrous network. We measured different cell types' propensity for cytoskeletal alignment in response to fiber scaffolds with differing levels of anisotropy. The results indicated that valvular interstitial cells on moderately anisotropic substrates have a higher propensity for cytoskeletal alignment than cardiomyocytes and vascular endothelial cells. However, all cell types displayed similar levels of alignment on more extreme (isotropic and highly anisotropic) fiber scaffold organizations. These data suggest that in the hierarchy of signals that dictate the spatiotemporal organization of a tissue, geometric cues within the ECM and cellular networks may homogenize behaviors across cell populations and demographics.

    

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5. The cerebral microvasculature: Basic and clinical perspectives on stroke and glioma

   https://doi.org/10.1111/micc.12671  

   Hoque, Maruf M. ; Abdelazim, Hanaa ; Jenkins‐Houk, Clifton ; Wright, Dawn ; Patel, Biraj M. ; Chappell, John C. ( November 2020 , Microcirculation)

   Microvascular networks are vital components of the cardiovascular system, performing many key roles in maintaining the health and homeostasis of the tissues and organs in which they develop. As discussed in this review, the molecular and cellular components within the microcirculation orchestrate critical processes to establish functional capillary beds, including organization of endothelial cell (EC) polarity, guiding investment of vascular pericytes (PCs), and building the specialized extracellular matrix (ECM) that comprises the vascular basement membrane (vBM). Herein, we further discuss the unique features of the microvasculature in the central nervous system (CNS), focusing on the cells contributing to the neurovascular unit (NVU) that form and maintain the blood‐brain barrier (BBB). With a focus on vascular PCs, we offer basic and clinical perspectives on neurovascular‐related pathologies that involve defects within the cerebral microvasculature. Specifically, we present microvascular anomalies associated with glioblastoma multiforme (GBM) including defects in vascular‐immune cell interactions and associated clinical therapies targeting microvessels (ie, vascular‐disrupting/anti‐angiogenic agents and focused ultrasound). We also discuss the involvement of the microcirculation in stroke responses and potential therapeutic approaches. Our goal was to compare the cellular and molecular changes that occur in the microvasculature and NVU, and to provide a commentary on factors driving disease progression in GBM and stroke. We conclude with a forward‐looking perspective on the importance of microcirculation research in developing clinical treatments for these devastating conditions.

    

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