Neovascular capacity of endothelial progenitor cells in the adult pulmonary circulation.

PULMONARY POSTNATAL NEOVASCULARIZATION or formation of de novo vessels in the adult lung has been controversial. Most of the argument has been focused on findings in the systemic circulation, which exhibits diverse degrees of angiogenesis (vessel formation from preexisting vessels) and arteriogenesis (collateral development proximal to a site of arterial occlusion). With the advent of stem cell plasticity, neovascularization was demonstrated to occur postnatally in skeletal and cardiac muscle, peripheral vasculature, adipose tissue, and the endometrium and during pathological conditions such as expansion of solid tumors. Furthermore, remodeling of the tunica intima and media is observed in the systemic circulation during atherosclerosis. Interestingly, parallel angiogenic responses are not frequently observed in the pulmonary circulation leading early investigators to theorize that the pulmonary circulation was quiescent, lacking the capacity to generate de novo vessels or undergo vascular remodeling. Moreover, during focal tissue hypoxia in the setting of idiopathic pulmonary arterial hypertension (IPAH), PAH secondary to fibrosis, or chronic obstructive pulmonary disease (COPD), the native pulmonary vasculature experiences a series of perturbations, which results in the loss, instead of the formation, of vessels. In 1847, Virchow (17) observed that under regional ischemia in the human lung, the systemic circulation restored circulation to nonperfused areas. From early studies, it was clear that the ischemic lung depends on the adjacent systemic circulation to provide necessary collateral circulation. More recently, neoangiogenesis by systemic vessels in the pulmonary artery vaso vasorum has been shown to occur in response to a variety of physiological and pathological stimuli (6). Despite the compelling support indicating that neovascularization of the pulmonary circulation occurs by extension of the systemic circulation, there are many studies supporting mechanisms that do not involve contribution of the systemic vasculature. Patients with scleroderma-induced vasculitis (4), pulmonary venoocclusive disease (15), idiopathic interstitial pneumonia (14), and acute respiratory distress syndrome (ARDS) survivors are important examples of lung neoangiogenesis that occur independent of the contribution from the systemic circulation. Moreover, experimental models of pneumonectomy in rats (9), caloric restriction in mice (13), intermittent levels of chronic hypoxia in rats (8), and lung tumorigenesis in dogs (11) further support that pulmonary neoangiogenesis arises in a systemic vasculature-independent manner. Although it is clear that neoangiogenesis and vascular remodeling develops within the pulmonary circulation, the origin of the cellular constituents that facilitate or contribute to this process is inconclusive. Recent evidence implicates several progenitors with the potential to engineer a proangiogenic environment or induce de novo vessel formation, including resident lung vascular cells (1, 10, 21), circulating bone marrow-derived cells such as endothelial progenitors (cEPCs; Ref. 16), and mesenchymal progenitors (fibrocytes; Ref. 7). Consistent with the concept that vascular progenitor cells arise from the bone marrow, pioneering work by Asahara et al. (2) resolved that isolated cells from the mononuclear fraction of the peripheral blood regulated neoangiogenesis in an ischemic experimental model. The cells identified by Asahara et al. (2) have been further characterized by their expression of the membrane proteins CD34, VEGFR2 (Flk-1), and CD133. In the lung, vascular progenitor cells are hypothesized to be recruited from the bone marrow or to exist within the tunica intima of blood vessels and capillaries (1), within the tunica adventitia of larger vessels (21), and within the tissue parenchyma (10). In agreement with the presence of circulating progenitor cells in the lung, patients with PAH demonstrate higher numbers of circulating CD34/CD133 cells compared with healthy controls. The isolated CD34/CD133 cells revealed a phenotype with enhanced ability to form angiogenic networks in vitro and displayed hyperproliferative, apoptosis-resistant behavior ex vivo (3, 12). In separate studies, increased numbers of CD133 cells were found within the pulmonary vasculature in humans with PAH and in vessels of a BMPR2 transgene murine model of PAH (19). The level of circulating mesenchymal progenitor CD45-/ collagen I-positive fibrocytes has been shown in PAH to correlate with a poor prognosis, indicating that circulating vascular and mesenchymal progenitors played a role in the pathogenesis of pulmonary vascular diseases. Disruption of pulmonary vascular flow such as that occurring during chronic pulmonary thromboembolism (CPT) has germane seminal contributions to the emergence of neoangiogenesis and remodeling within the occlusive lesion. Lung specimens obtained from patients with CPT reveal that organized thromboembolic lesions remodel into fibrotic tissue, instead of self-resolving, reminiscent of plexiform lesions (5). Interestingly, the fibrotic lesions often exhibit mild inflammatory infiltrates and display recanalized or vascularized lumens (5). These observations are important considering that in the lung, cellular inflammatory constituents regulate neoangiogenesis and neointimal remodeling. In a mouse model of chronic pulmonary artery ligation, lymphocytes were restrictive, whereas monocytes/ macrophages promoted neovascularization (18). Based on the evidence found in the literature, it is plausible that the neoangiogenesis and remodeling processes occurring in the CPT lesions may be impacted by the contribution of vascular proAddress for reprint requests and other correspondence: D. F. Alvarez, Internal Medicine, Pharmacology, and Center for Lung Biology, Univ. of South Alabama, MSB 3322, Mobile, AL 36688-0002 (e-mail: [email protected]). Am J Physiol Lung Cell Mol Physiol 296: L868–L869, 2009; doi:10.1152/ajplung.00103.2009.