Chronic obstructive pulmonary disease (COPD) is the third leading cause of mortality in the United States. COPD often is exacerbated by vasculopathy, which substantially worsens prognosis and limits survival. Vasculopathy is characterized by remodeling and loss of microvessels. Recent evidence has also highlighted a role for the alterations to the microvasculature during the early pathogenesis and heterogeneity of COPD, although the underlying mechanisms are not defined. The goal of this proposal is to address this knowledge gap by defining the molecular mechanisms whereby reciprocal mesenchymal progenitor-endothelial cell interactions regulate pulmonary microvascular structure and the development of COPD. In the last funding cycle, we reported the existence of a novel population of mesenchymal progenitor cells (MPC) which serve as progenitors for pericytes and therefore are required to maintain microvascular homeostasis. We further reported that Wnt/?-catenin signaling was an important regulator of this MPC function. However, how increased Wnt signaling in MPC, production of its modulator Dkk1 and the development of vasculopathy impacts surfaces for gas exchange and the pathophysiology of COPD is unknown. Therefore, understanding Wnt signaling in MPC, will be important to facilitate microvascular and tissue function. The novel premise of this proposal is that enhanced Wnt/?-catenin signaling within MPCs indirectly leads to emphysema and COPD by altering normal MPC-microvascular endothelial cell (MVEC) interactions. We hypothesize that activation of Wnt/?-catenin in MPC exacerbates the onset of COPD via 1) increased production of Dkk1 and b) a paracrine effect of Dkk1 on microvascular endothelial cell function. We will test that activation of Wnt/?- catenin in MPCs leads to COPD via increased MPC expression of Dkk1 and subsequent paracrine alteration of microvascular endothelial cell-fate specification. To test whether MPC expression of ?-catenin and Dkk1 are critical for maintenance of MPC-MVEC cross talk and tissue remodeling in COPD, we will conditionally knock down or overexpress Dkk1 and ?-catenin in MPC and expose mice to smoke or vascular injury. We will employ novel models of lineage analyses, optical coherence tomography (OCT), histological indices of angiogenesis and measures of barrier function. We will also test that maintenance of MPC-MVEC interaction via manipulation of Dkk1 signaling will attenuate loss of microvascular function and tissue structure following injury. We will manipulate Dkk1/Wnt signaling in human and mouse lung MPCs in vitro and inhibit Dkk1 signaling in murine models in vivo, to evaluate the mechanism by which MVEC function is affected. These studies will determine whether modulation of MPC, or inhibition / knockout Dkk1 signaling in MVEC is a viable target to promote microvascular function and attenuate COPD. Our proposed studies will advance the field of by defining Wnt dependent mechanisms by which MPC regulate microvascular endothelial function and identify targets to reverse vasculopathy in COPD, by repurposing of FDA approved DKK1 modulators.
It is generally assumed that vasculopathies associated with emphysema/COPD are attributable to deficient vascular endothelium or smooth muscle cell phenotypes. We challenge this paradigm by defining an adult mesenchymal pericyte progenitor (ABCG2pos MPC) that regulates both microvascular function during tissue homeostasis and adaptive angiogenesis in response to injury, capable of exacerbating COPD. Therefore, the ABCG2posMPC compartment of lung is a previously unstudied target that will be exploited in our proposed studies to identify new pathways relevant to the pathobiology of COPD.
