Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF ₁₆₄

Abstract

Significance Inducing the growth of new blood vessels by specific factors is an attractive strategy to restore blood flow in ischemic tissues. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis, yet clinical trials of VEGF gene delivery failed. Major challenges include the need to control the tissue distribution of factor dose and the duration of expression. Here, we developed a highly tunable fibrin-based platform to precisely control the dose and duration of VEGF protein delivery in tissues. Optimized delivery of fibrin-bound VEGF ensured normal, stable, and functional angiogenesis and improved perfusion of ischemic tissues, without genetic modification and with limited duration of VEGF delivery. These findings suggest a strategy to improve both safety and efficacy of therapeutic angiogenesis.

Shock Wave Treatment Enhances Cell Proliferation and Improves Wound Healing by ATP Release-coupled Extracellular Signal-regulated Kinase (ERK) Activation

“…A standard rodent ischemic epigastric flap model was modified to study the effect of shock wave treatment on ischemia-impaired wound healing (37). 4 In brief, rats were anesthetized in an inhalation box using isoflurane (2.5 volume %).…”

Mechanotransduction and Growth Factor Signalling to Engineer Cellular Microenvironments

“…[35] Sobel et al identified the heparin II binding region of fibronectin (FNIII [12][13][14] ) as a VEGF binding site. [36] They reported that fibronectin fragments including FNIII [9][10] (integrin binding region) and FNIII [12][13][14] endothelial cell migration, proliferation and signalling. [36] Martino and Hubbell generalized this result to show that FNIII [12][13][14] not only bound VEGF but was actually a highly promiscuous region with affinity towards GFs from different families.…”

“…functionalized with two recombinant fragments of fibronectin joined together, FNIII [9][10] , to promote integrin binding and cell adhesion, [35] and FNIII [12][13][14] , to bind GFs. [37] They showed that the system enhanced the formation of tube-like structures in endothelial cells (with VEGF-A), sprouting of smooth muscle cells (with platelet-derived growth factor (PDGF)-BB) and differentiation of mesenchymal stem cells (MSC) (with BMP-2).…”

“…[41][42][43][44] We noted that FNIII [12][13][14] (GF binding region) is located next to the integrin binding region (FNIII [9][10] ) with potential for synergistic integrin/GF signaling. However, for this to be exploited, fibronectin must be open, unfolded, to have the relevant regions available for interaction (Figure 3b).…”

“…ethyl -PEA, butyl -PBA, hexyl -PHA) promoted fibronectin assembly into nanonetworks (Figure 3b). [45][46][47] This assembled fibronectin structure has the ability to present GFs in synergy with α 5 β 1 integrins, i.e., the molecule is open and FNIII [9][10] and III [12][13][14] regions are simultaneously available for interaction. Indeed, using atomic force microscopy we showed that BMP-2 binds fibronectin nanonetworks previously assembled on PEA and then promotes co-localization of integrins and GF receptors resulting in enhanced canonical Smad signaling (Figure 3c).…”