Perivascular Mast Cells Govern Shear Stress-Induced Arteriogenesis by Orchestrating Leukocyte Function

Abstract

The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit(+)/CXCR-4(+) cells stimulate arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases.

Teriparatide Treatment Improves Bone Defect Healing Via Anabolic Effects on New Bone Formation and Non-Anabolic Effects on Inhibition of Mast Cells in a Murine Cranial Window Model

“…Therefore, large vascular smooth muscle containing vessels are not required for recruitment, differentiation, and/or retention of mast cells in critical bone defects as we previously proposed . Moreover, these finding suggest that mast cells may be a source of the vascular endothelial growth factors and angiopoietin‐2 that drives angiogenesis and subsequent arteriogenesis, as has been reported in other models . Thus, formally testing this, and elucidating the mechanisms responsible for mast cell accumulation in critical defects remain important areas for future investigation.…”

“…In contrast, perivascular mast cells play a central role in regulating shear stress–induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release. This leads to a vicious cycle of mast cell recruitment and activation, and stimulation of arteriogenesis via recruitment of neutrophils, monocytes, and T cells …”

Characterization of mast cell‐derived rRNA‐containing microvesicles and their inflammatory impact on endothelial cells

“…Our previous studies showed that MCs play a regulatory role in arteriogenesis, the process of shear stress‐induced growth of collateral vessels (11). Following the induction of arteriogenesis by FAL in mice for 24 h, immunohisto‐chemical analysis of adductor muscle tissue revealed the presence of c‐kit‐, tryptase‐, and rRNA‐positive MCs around growing collaterals.…”

“…Using the murine hind limb model of arteriogenesis, following FAL, the subsequent reperfusion was significantly increased in mice that underwent procedures to activate MCs in vivo , particularly using degranulating agents such as compound 48/80. Furthermore, under these circumstances, mobilized and degranulated MCs were located in close proximity to growing collateral vessels, as compared with sham‐operated controls (11). Our follow‐up study now demonstrates that rRNA‐containing MCs and free eRNA were located in close proximity to growing collateral arteries.…”

Polymer scaffold architecture is a key determinant in mast cell inflammatory and angiogenic responses

“…Similar to macrophages, mast cells originate in the bone marrow from the common myeloid progenitor, migrate to the vasculature as a mast cell progenitor, and fully mature in tissues, where their functional phenotype is plastic and determined by the microenvironment. Mature mast cells are often situated perivascularly and can have profound effects on vascular tone, edema, and angiogenesis . When angiogenesis occurs during remodeling, it is preceded or accompanied by macrophage and neutrophil influx that has been argued to be mast cell‐mediated .…”