Vascular Regeneration by Local Growth Factor Release Is Self-Limited by Microvascular Clearance

Background— The challenge of angiogenesis science is that stable sustained vascular regeneration in humans has not been realized despite promising preclinical findings. We hypothesized that angiogenic therapies powerfully self-regulate by dynamically altering tissue characteristics. Induced neocapillaries increase drug clearance and limit tissue retention and subsequent angiogenesis even in the face of sustained delivery. Methods and Results— We quantified how capillary flow clears fibroblast growth factor after local epicardial delivery. Fibroblast growth factor spatial loading was significantly reduced with intact coronary perfusion. Penetration and retention decreased with transendothelial permeability, a trend diametrically opposite to intravascular delivery, in which factor delivery depends on vascular leak, but consistent with a continuum model of drug transport in perfused tissues. Model predictions of fibroblast growth factor sensitivity to manipulations of its diffusivity and transendothelial permeability were validated by conjugation to sucrose octasulfate. Induction of neocapillaries adds pharmacokinetic complexity. Sustained local fibroblast growth factor delivery in vivo produced a burst of neovascularization in ischemic myocardium but was followed by drug washout and a 5-fold decrease in fibroblast growth factor penetration depth. Conclusions— The very efficacy of proangiogenic compounds enhances their clearance and abrogates their pharmacological benefit. This self-limiting property of angiogenesis may explain the failures of promising proangiogenic therapies.National Institutes of Health (U.S.) (Grant R01 GM 49039

Heterochromatin and the molecular mechanisms of 'parent-of-origin' effects in animals.

Twenty five years ago it was proposed that conserved components of constitutive heterochromatin assemble heterochromatinlike complexes in euchromatin and this could provide a general mechanism for regulating heritable (cell-to-cell) changes in gene expressibility. As a special case, differences in the assembly of heterochromatin-like complexes on homologous chromosomes might also regulate the parent-of-origin-dependent gene expression observed in placental mammals. Here, the progress made in the intervening period with emphasis on the role of heterochromatin and heterochromatin-like complexes in parent-of-origin effects in animals is reviewed

Local PK and PD of angiogenic growth factors in myocardial tissue

Thesis (Ph. D.)--Harvard-MIT Division of Health Sciences and Technology, 2009.Cataloged from PDF version of thesis.Includes bibliographical references.Early enthusiasm over angiogenic therapy, a method to induce vascular regeneration to treat ischemic tissue with growth factors, has been tempered by a series of unsuccessful clinical trials with limited late efficacy and a wide range of mixed results. This thesis was designed to examine critically whether the lack of late efficacy of local delivery of angiogenic factors could be explained by a comprehensive understanding of local pharmacokinetics (PK) and pharmacodynamics (PD) in the myocardial tissue. Our central hypothesis is that early success at inducing vessel growth powerfully self-regulates angiogenic therapies by dynamically altering local tissue pharmacokinetic properties and hinders long-term efficacy. We used a multipronged approach to investigate this hypothesis. We characterized the baseline local myocardial PK through a series of ex-vivo isolated heart studies and mathematical analysis, examined the local coupling of PK and PD with an in-vivo ischemic heart model, created a computational model of myocardial PK and PD to predict distribution of growth factors and their biologic effects, discussed implications and future studies. Our findings suggest that microvascular washout impedes myocardial drug transport, early angiogenic response further exacerbates drug washout and is likely responsible for late vessel regression, modulating drug PK properties to mitigate drug clearance through washout can enhance late tissue response. These results imply that local PK-PD interdependence should be carefully examined to improve clinical efficacy of angiogenic therapy with local angiogenic growth factor delivery.by Kha N. Le.Ph.D

Transport of FGF-2 in myocardium

Thesis (S.M.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2002.Includes bibliographical references (leaves 91-95).An emerging approach for the treatment of ischemic heart disease is the induction of angiogenesis by means of the locally delivering growth factors to the myocardium. When deposited within heart tissue the compounds elicit a vascular response that is hoped to perfuse ischemic myocardium. There is, however, little quantitative data on macromolecular transport in myocardium, their fate after being delivered, how their transport is affected by structural properties of myocardial tissue, and in-vivo conditions such as the convection of blood in the highly vascular capillary network. Attempts to find effective ways of delivering therapeutic macromolecules to myocardium that could maximize the impact of the agents and minimize systemic toxicity and adverse side effects have been hampered by the minimal understanding of transport in the complex myocardial tissue under varying in-vivo conditions. This thesis investigates macromolecular transport mechanism in the myocardium by examining the role of diffusion, equilibrium average tissue binding, and capillary convection. Epidermal growth factor (EGF) and basic fibroblast growth factor (FGF-2) were chosen as model growth factor because of their potency of inducing endothelial mitosis and angiogenesis invitro. The "effective" diffusivity and partition coefficient of radiolabeled EGF and FGF-2 in rat myocardium were obtained with a diffusion cell in minimal time assuring tissue integrity and protein stability. A three-dimensional continuum pharmacokinetic model that takes into account realistic coronary capillary network configuration and morphometry was constructed to simulate transport of generic macromolecules in a highly vascular tissue such as the myocardium. Partition coefficients of EGF and FGF-2 were 0.26 and 1.34, and diffusivities 1.42 and 4.58 [mu]m2/s, respectively. The impact of vasculature was evaluated in a computational model constructed based on these findings. At steady state equilibrium, total drug deposition and penetration depth of macromolecules in physiologic range in myocardium were shown to be much less than that for solid tissue that is not perfused by capillary network. Drug transport varied inversely as functions of intimal permeability and capillary density. Results from this study provided insights into the design of myocardial drug delivery systems, and drug engineering with a hope to better angiogenic treatment for ischemic heart disease.by Kha N. Le.S.M

Severe COVID-19 during pregnancy treated with pulse corticosteroid therapy and mid-trimester termination: A case report

Background: At the early stage of the pandemic, severe COVID-19 was thought to be rare among pregnant women. However, cumulating data showed that gestational state is a risk factor for severe pneumonia, particularly due to the hyperinflammatory state. Recent reports suggested the efficacy of pulse corticosteroids in stopping the cytokine storm in people infected with SARS-CoV-2, but limited data exists regarding its use in pregnant women. Moreover, pregnancy termination is a treatment option in this population, but it has been reported mainly in the third trimester and rarely in the second trimester. Case Presentation: A 37-year-old woman infected with SARS-CoV-2 at 23 weeks of gestation presented with fatigue and dyspnea but soon deteriorated to severely acute respiratory failure and cytokine storm requiring mechanical ventilation combined with hemodialysis just one day after hospitalization. Low-dose corticosteroids and antibiotics were initiated, followed by antiviral therapy, anticoagulant and high-dose corticosteroid therapy. On hospital day 3, a decision to terminate her pregnancy was made; termination led to significant improvement in her clinical condition and a gradual decrease in demand for oxygen supplementation as well as the corticosteroid dose. She was discharged two weeks after admission. Conclusions: Due to the specific immune response, pregnant women with COVID-19 may differ from others in their clinical presentation, especially the probability of classic acute respiratory distress syndrome (ARDS). This report provides evidence related to the efficacy of pulse corticosteroids on this group and the influence of the mid-trimester termination on recovery