Dynamic Multiscale Regulation of Perfusion Recovery in Experimental Peripheral Arterial Disease: A Mechanistic Computational Model.

In peripheral arterial disease (PAD), the degree of endogenous capacity to modulate revascularization of limb muscle is central to the management of leg ischemia. To characterize the multiscale and multicellular nature of revascularization in PAD, we have developed the first computational systems biology model that mechanistically incorporates intracellular, cellular, and tissue-level features critical for the dynamic reconstitution of perfusion after occlusion-induced ischemia. The computational model was specifically formulated for a preclinical animal model of PAD (mouse hindlimb ischemia [HLI]), and it has gone through multilevel model calibration and validation against a comprehensive set of experimental data so that it accurately captures the complex cellular signaling, cell-cell communication, and function during post-HLI perfusion recovery.

Epigenetic regulators of the revascularization response to chronic arterial occlusion.

Peripheral arterial disease (PAD) is the leading cause of lower limb amputation and estimated to affect over 202 million people worldwide. PAD is caused by atherosclerotic lesions that occlude large arteries in the lower limbs, leading to insufficient blood perfusion of distal tissues. Given the severity of this clinical problem, there has been long-standing interest in both understanding how chronic arterial occlusions affect muscle tissue and vasculature and identifying therapeutic approaches capable of restoring tissue composition and vascular function to a healthy state.

Exposure of Endothelium to Biomimetic Flow Waveforms Yields Identification of miR-199a-5p as a Potent Regulator of Arteriogenesis.

Arteriogenesis, the growth of endogenous collateral arteries bypassing arterial occlusion(s), is a fundamental shear stress-induced adaptation with implications for treating peripheral arterial disease (PAD). Nonetheless, endothelial mechano-signaling during arteriogenesis is incompletely understood. Here we tested the hypothesis that a mechanosensitive microRNA, miR-199a-5p, regulates perfusion recovery and collateral arteriogenesis following femoral arterial ligation (FAL) via control of monocyte recruitment and pro-arteriogenic gene expression.

MicroRNA-146a Regulates Perfusion Recovery in Response to Arterial Occlusion Arteriogenesis.

The growth of endogenous collateral arteries that bypass arterial occlusion(s), or arteriogenesis, is a fundamental shear stress-induced adaptation with implications for treating peripheral arterial disease. MicroRNAs (miRs) are key regulators of gene expression in response to injury and have strong therapeutic potential. In a previous study, we identified miR-146a as a candidate regulator of vascular remodeling.

DNA Methyltransferase 1-Dependent DNA Hypermethylation Constrains Arteriogenesis by Augmenting Shear Stress Set Point.

Background: Arteriogenesis is initiated by increased shear stress and is thought to continue until shear stress is returned to its original "set point." However, the molecular mechanism(s) through which shear stress set point is established by endothelial cells (ECs) are largely unstudied. Here, we tested the hypothesis that DNA methyltransferase 1 (DNMT1)-dependent EC DNA methylation affects arteriogenic capacity via adjustments to shear stress set point.

Vascular growth responses to chronic arterial occlusion are unaffected by myeloid specific focal adhesion kinase (FAK) deletion.

Arteriogenesis, or the lumenal expansion of pre-existing arterioles in the presence of an upstream occlusion, is a fundamental vascular growth response. Though alterations in shear stress stimulate arteriogenesis, the migration of monocytes into the perivascular space surrounding collateral arteries and their differentiation into macrophages is critical for this vascular growth response to occur. Focal adhesion kinase's (FAK) role in regulating cell migration has recently been expanded to primary macrophages.

Mechanisms of Amplified Arteriogenesis in Collateral Artery Segments Exposed to Reversed Flow Direction.

Objective: Collateral arteriogenesis, the growth of existing arterial vessels to a larger diameter, is a fundamental adaptive response that is often critical for the perfusion and survival of tissues downstream of chronic arterial occlusion(s). Shear stress regulates arteriogenesis; however, the arteriogenic significance of reversed flow direction, occurring in numerous collateral artery segments after femoral artery ligation, is unknown. Our objective was to determine if reversed flow direction in collateral artery segments differentially regulates endothelial cell signaling and arteriogenesis.

Computational Network Model Prediction of Hemodynamic Alterations Due to Arteriolar Rarefaction and Estimation of Skeletal Muscle Perfusion in Peripheral Arterial Disease.

Objective: To estimate the relative influence of input pressure and arteriole rarefaction on gastrocnemius muscle perfusion in patients with PAD after exercise and/or percutaneous interventions.

Methods: A computational network model of the gastrocnemius muscle microcirculation was adapted to reflect rarefaction based on arteriolar density measurements from PAD patients, with and without exercise. A normalized input pressure was applied at the feeder artery to simulate both reduced and restored ABI in the PAD condition.

Monocytes are recruited from venules during arteriogenesis in the murine spinotrapezius ligation model.

Objective: Chronic arterial occlusion results in arteriogenesis of collateral blood vessels. This process has been shown to be dependent on the recruitment of growth-promoting macrophages to remodeling collaterals. However, the potential role of venules in monocyte recruitment during microvascular arteriogenesis is not well demonstrated.

Reduction of burn progression with topical delivery of (antitumor necrosis factor-α)-hyaluronic acid conjugates.

In this study, we explored whether topical application of antibodies targeting tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) conjugated to hyaluronic acid (HA) could reduce the extension of necrosis by modulating inflammation locally in a partial-thickness rat burn model. Partial-thickness to deep partial-thickness burn injuries present significant challenges in healing, as these burns often progress following the initial thermal insult, resulting in necrotic expansion and increased likelihood of secondary complications. Necrotic expansion is driven by a microenvironment with elevated levels of pro-inflammatory mediators, and local neutralization of these using antibody conjugates could reduce burn progression.