No abstract

Sunitinib malate is a multi-targeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact PDGFR signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anti-cancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.

Blood vessels have long been known to respond to hemodynamic force, and several mechanotransduction pathways have been identified. However, only recently have we begun to understand the effects of hemodynamic force on embryonic development. In this review, we will discuss specific examples illustrating the role of hemodynamic force during the development of the embryo, with particular focus on the development of the vascular system and the morphogenesis of the heart. We will also discuss the important functions served by mechanotransduction and hemodynamic force during placentation, as well as in regulating the maintenance and division of embryonic, hematopoietic, neural, and mesenchymal stem cells. Pathological misregulation of mechanosensitive pathways during pregnancy and embryonic development may contribute to the occurrence of cardiovascular birth defects, as well as to a variety of other diseases, including preeclampsia. Thus, there is a need for future studies focusing on better understanding the physiological effects of hemodynamic force during embryonic development and their role in the pathogenesis of disease.

Injury to the neurovasculature is a feature of brain injury and must be addressed to maximize opportunity for improvement. Cerebrovascular dysfunction, manifested by reduction in cerebral blood flow (CBF), is a key factor that worsens outcome after traumatic brain injury (TBI), most notably under conditions of hypotension. We report here that a new class of antioxidants, poly(ethylene glycol)-functionalized hydrophilic carbon clusters (PEG-HCCs), which are nontoxic carbon particles, rapidly restore CBF in a mild TBI/hypotension/resuscitation rat model when administered during resuscitation—a clinically relevant time point. Along with restoration of CBF, there is a concomitant normalization of superoxide and nitric oxide levels. Given the role of poor CBF in determining outcome, this finding is of major importance for improving patient health under clinically relevant conditions during resuscitative care and it has direct implications for the current TBI/hypotension war-fighter victims in the Afghanistan and Middle East theaters. The results also have relevancy in other related acute circumstances such as stroke and organ transplantation.

The vasculature of an organism has the daunting task of connecting all the organ systems to nourish tissue and sustain life. This complex network of vessels and associated cells must maintain blood flow but constantly adapt to acute and chronic changes within tissues. While the vasculature has been studied for over a century, we are just beginning to understand the processes that regulate its formation and how genetic hierarchies are influenced by mechanical and metabolic cues to refine vessel structure and optimize efficiency. As we gain insights into the developmental mechanisms, it is clear that the processes that regulate blood vessel development can also enable the adult to adapt to changes in tissues that can be elicited by exercise, aging, injury, or pathology. Thus, research in vessel development has provided tremendous insights into therapies for vascular diseases and disorders, cancer interventions, wound repair and tissue engineering, and in turn, these models have clearly impacted our understanding of development. Here we provide an overview of the development of the vascular system, highlighting several areas of active investigation and key questions that remain to be answered.