Vascular cell and extracellular matrix interactions: Implications for vascular regeneration and disease modeling

Abstract

The human body depends on a specialized perfused blood vessel (vascular) network to provide all cells with oxygen and nutrients. Via the complex process of angiogenesis, formation of new small blood vessels from existing small blood vessels leads to the constant remodelling of this vascular network. This tightly regulated process highlights the complex interactions between vascular cells and their direct environment; the extracellular matrix (ECM). These interactions are essential for blood vessel stability, vascular (pathological)development and vascular regeneration. A major challenge in regenerative medicine is the development of tissues with a functional vascular network to provide all cells with oxygen. Blood vessels can be mimicked in the laboratory, creating in vitro models. These models offer scientists the opportunity to unravel complex vascular interactions during development in health and disease. The studies described in this thesis highlights the important interactions between two vascular cell types, the endothelial cell (EC) and the mural cell, in vascular development and vessel stabilization in health and disease. In more detail; the endothelial receptor Frizzled 5 may be an interesting target for vascular regenerative strategies since this receptor is involved in blood vessel formation. Since EC and pericyte interaction is key in vascular homeostasis, we studied the influence of ECs on pericyte phenotype and maturation by describing the differences in the transcriptome profile of pericytes cultured in presence and absence of ECs. We reviewed the essential role of pericytes and their versatile functions in vascular stabilization and regeneration. Furthermore, we attribute an important role of the direct ECM environment in regulating blood vessel and renal tubule development. Proteomics identified ECM components in developing tissue which could function as interesting candidates for regenerative applications. Overall, these fundamental insights can be implemented in diverse regenerative applications including the development of innovative and complex human in vitro vascular models. Since progressive pathological ECM deposition (fibrosis) is common in multiple diseases, including left ventricular diastolic dysfunction, examining ECM regulators such as matrix metalloproteinases (MMPs) could give insight in this dynamic process. We reviewed the current literature focusing on validated animals models of left ventricular diastolic dysfunction were cardiac fibrosis and MMPs are studied. We also describe the use of two models that focus on vascular research and better mimic the complex human environment. Using a rodent model of diastolic dysfunction with multiple comorbidities such as hypertension, obesity and renal dysfunction, we studied fibrosis formation and microvascular dysfunction in both heart and kidney tissue. Last, we described the validation of a novel in vitro model mimicking a 3D blood vessel surrounded by supporting pericytes and ECM which can be easily imaged and perfused. Pro-inflammatory conditions showed the interaction of circulating immune cells and the vasculature. These models are clinically more relevant by combining multiple characteristics of the complex vascular network, including relevant cell types and well-known risk factors, and provide the opportunity to study potential therapies and regeneration. The implementation of results described in this thesis lead to a better translation of research data to clinical applications.