Background-Our aim was to observe ultrasound-induced intravascular microbubble destruction in vivo and to characterize any resultant bioeffects. Methods and Results-Intravital microscopy was used to visualize the spinotrapezius muscle in 15 rats during ultrasound delivery. Microbubble destruction during ultrasound exposure caused rupture of Յ7-m microvessels (mostly capillaries) and the production of nonviable cells in adjacent tissue. The number of microvessels ruptured and cells damaged correlated linearly (PϽ0.001) with the amount of ultrasound energy delivered. Conclusions-Microbubbles can be destroyed by ultrasound, resulting in a bioeffect that could be used for local drug delivery, angiogenesis, and vascular remodeling, or for tumor destruction. (Circulation. 1998;98:290-293.)

Microvessel ruptures caused by insonification of microbubbles in vivo may provide a minimally invasive means for delivering colloidal particles and engineered red blood cells across the endothelial lining of a targeted tissue region.

Most animal models of chronic pressure ulcers were designed to study only the role of ischemic injury in wound formation, often using single applications of constant pressure. The purpose of this study was to develop and characterize a reproducible model of cyclic ischemia-reperfusion injury in the skin of small un-anesthetized animals using clinically relevant pressures and durations. Ischemia-reperfusion injury was created in a 9 cm2 region of dorsal skin in male rats by periodically compressing skin under a pressure of 50 mm Hg using an implanted metal plate and an overlying magnet. We varied the total number of ischemia-reperfusion cycles, examined the effect of varying the frequency and duration of ischemic insult, and compared ischemia-induced injury to ischemia-reperfusion-induced injury with this model. Tissue injury increased with an increasing number of total ischemia-reperfusion cycles, duration of ischemia, and frequency of ischemia-reperfusion cycles. This model generates reproducible ischemia-reperfusion skin injury as characterized by tissue necrosis, wound thickness, leukocyte infiltration, transcutaneous oxygen tension, and wound blood flow. Using this model, the biological markers of ischemia-reperfusion-induced wound development can be studied and therapeutic interventions can be evaluated in a cost-effective manner.

The microvasculature is an extremely adaptable structure that is capable of architectural and functional adjustments in response to multiple biochemical and mechanical stimuli. Inadequate or inappropriate adjustments often result in pathophysiology. Recent work has brought increasing recognition of the importance of microvascular remodeling in widespread disease states such as hypertension, tumor growth, diabetes, and progressive coronary artery occlusion. Much work has been done to characterize the cells and molecules with putative roles in microvascular remodeling, but little is known regarding the mechanotransduction processes that might link hemodynamic stresses such as wall shear stress and circumferential wall stress to structural and functional changes in vivo. Two primary approaches have been employed: in vitro studies that use cultured cells and allow molecular biologic analysis of signaling pathways and gene expression; and in vivo experiments aimed at understanding vessel adaptations in the intact tissue. This article reviews the structural adaptations exhibited by microvessels and the information available from in vitro and in vivo approaches. The formation of new arterioles in intact tissues is examined in detail as an example of integrative work, and the prospects for new technologies are discussed. This is a time of great opportunity for bidirectional exchange between basic in vitro advances and in vivo experimentation. This exchange will be essential in generating new understanding of the role of mechanical stresses in microvascular remodeling.

The results indicate that NG2 is expressed by all perivascular cells along arterioles, and its absence denotes a venule-specific phenotype. These results identify for the first time a marker that differentiates venous smooth muscle and pericytes from other capillary- and arteriole-associated perivascular cells.

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Remodeling of microvascular networks in mammals is critical for physiological adaptations and therapeutic revascularization. Cellular behaviors such as proliferation, differentiation, and migration are coordinated in these remodeling events via combinations of biochemical and biomechanical signals. We developed a cellular automata (CA) computational simulation that integrates epigenetic stimuli, molecular signals, and cellular behaviors to predict microvascular network patterning events. Over 50 rules obtained from published experimental data govern independent behaviors (including proliferation, differentiation, and migration) of thousands of interacting cells and diffusible growth factors in their tissue environment. From initial network patterns of in vivo blood vessel networks, the model predicts emergent patterning responses to two stimuli: 1) network-wide changes in hemodynamic mechanical stresses, and 2) exogenous focal delivery of an angiogenic growth factor. The CA model predicts comparable increases in vascular density (370+/-29 mm/mm3) 14 days after treatment with exogenous growth factor to that in vivo (480+/-41 mm/mm3) and approximately a twofold increase in contractile vessel lengths 5-10 days after 10% increase in circumferential wall strain, consistent with in vivo results. The CA simulation was thus able to identify a functional patterning module capable of quantitatively predicting vessel network remodeling in response to two important epigenetic stimuli.

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