The extracellular matrix (ECM) is a complex biological system that plays a key role in regulating tissue development, growth and homeostasis by interacting with resident cells and by modulating the release of soluble signals. Tissue degeneration is a shared pathology of multiple human diseases that remains an unmet medical challenge, despite significant research effort. Aortic aneurysms are illustrative examples of diseases associated with tissue degeneration. These life-threatening pathologies are characterized by progressive vessel dilation associated with smooth muscle cell (SMC) dysfunction, localized inflammatory infiltrates and destructive (maladaptive) ECM remodeling that, together, predispose the arterial wall to tear (dissection) and rupture. Consistent with the degenerative nature of the disease, mutations in molecules normally implicated in supporting tissue integrity and homeostasis, such as components of the ECM, SMC cytoskeleton and TGFb signaling pathways, account for inherited forms of thoracic aortic aneurysm and acute aortic dissection (TAAD). Prevention of untimely death from TAAD currently relies on early detection by routine imaging and prophylactic repair by surgical procedures. Unfortunately, disease progression is highly heterogeneous, clinical outcome is unpredictable, therapeutic options are limited and surgical repair carries significant morbidity/mortality risks.

Our laboratory employs systems therapeutics in combination with experimental approaches in genetically engineered mice as an unbiased tissue-level strategy to identify TAAD-causing pathways in Marfan syndrome (MFS) that can be efficaciously targeted by combinatorial treatments with repurposed drugs. MFS is an informative genetic model of severe arterial disease that is caused mutations in fibrillin-1, a dual-function component of the architectural matrix. The first role of fibrillin-1 assemblies (microfibrils and elastic fibers) is structural for they endow tissues with tensile strength and elasticity, transmit forces across them and demarcate functionally discrete areas within them. The second role is instructive in that these macroaggregates modulate a large variety of sub-cellular processes by interacting with mechanosensors, and integrin and syndecan receptors, and by modulating the bioavailability of local TGFβ signals.

Major projects relevant to TAAD pathophysiology and therapeutics include the characterization of (1) how fibrillin-1 deficiency impacts the cross-communication between intimal endothelial cells (EnCs) and medial SMCs that regulates vascular tone in response to cyclic hemodynamic load; and (2) how pharmacological manipulations of vascular tone-regulating signals affects TAAD progression at the cellular and tissue levels. The long-term goal of our studies is to transform MFS from a deadly disease that requires surgical intervention to a chronic condition that can be managed by drug therapy.