Sprouting angiogenesis contributes to coronary collateral growth induced by repetitive ischemia in adult mice

Sprouting angiogenesis contributes to coronary collateral growth induced by repetitive ischemia in adult mice

Jamaiyar A;Juguilon C;Richardson D;Gadd J;Wang T;Enrick M;Goodner R;Chilian W;Yin L

Faseb Journal

2020

2020-04

In the United States, coronary heart diseases (CHD) are the leading cause of mortality and morbidity. A well‐developed coronary collateral circulation ameliorates the consequences of CHD, reducing the incidence of sudden death and infarct sizes following coronary occlusion. Stimulation of coronary collateral growth (CCG) is also an alternative therapeutic approach to patients with intractable angina pectoris. The importance of CCG is undisputable, but the process and mechanism underlying CCG is unclear. We developed a mouse model of CCG induced by repetitive ischemia (RI) and validated CCG by contrast echocardiography to measure the coronary blood flow in the normal zone (NZ) and the collateral dependent zone (CZ). We also used Micro‐CT scans to reconstruct the coronary vasculature in 3D and quantify CCG. In this study, we crossed ROSA mT/mG double fluorescent reporter mice with cell type‐specific cre mice to investigate the roles that different cell‐types play at various stages of CCG. Mice were subjected to the RI protocol and their cardiac function and coronary blood flow was measured by echocardiography. Following sacrifice, hearts were fixed for immunostaining or imaging under confocal and multiphoton microscopy. In ROSA mT/mG floxed, Apln cre mouse hearts, large vessels (diameter of 20–50 μm) expressing GFP were identified in the collateral dependent zone in the early stage of RI, indicating that they originated from sprouting endothelial cells. At the end of RI, a complete network of these vessels was observed anastomosing with existing vasculature from the NZ. Immunostaining revealed an outer layer of smooth muscle cells in these vessels, suggesting the arteriogenesis or arterialization. Interestingly, in ROSA mT/mG floxed, Lyz2 cre mouse hearts, GFP expressing myeloid cells were observed in high numbers around newly formed large vessels, suggesting that immune cell recruitment occurs in the early stages of CCG. Our preliminary data show that coronary collaterals form in response to RI, are of microvascular origin and are associated with early recruitment of immune cells to the CZ. Our further study will focus on the process of CCG in greater detail at the molecular and cellular level, potentially leading toward a therapeutic application of induced CCG in patients of ischemic heart diseases.

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