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VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34⁺ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells

Seiichiro Sakao^*,,1, Laimute Taraseviciene-Stewart^*, Carlyne D. Cool, Yuji Tada, Yasunori Kasahara, Katsushi Kurosu, Nobuhiro Tanabe, Yuichi Takiguchi, Koichiro Tatsumi, Takayuki Kuriyama and Norbert F. Voelkel^*

^* Pulmonary Hypertension Center and

Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado, USA; and

Department of Respirology (B2), Graduate School of Medicine, Chiba University, Chiba, Japan

¹Correspondence: Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1–8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail: sakaos{at}faculty.chiba-u.jp

Severe pulmonary hypertension (PH) is characterized by complex precapillary arteriolar lesions, which contain phenotypically altered smooth muscle (SM) and endothelial cells (EC). We have demonstrated that VEGF receptor blockade by SU5416 {3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-indolin 2-one} in combination with chronic hypoxia causes severe angioproliferative PH associated with arterial occlusion in rats. We postulate that endothelial-mesenchymal transdifferentiation can take place in the occlusive lesions and that endothelium-derived mesenchymal cells can further differentiate toward a SM phenotype. To examine this hypothesis, we incubated human pulmonary microvascular endothelial cells (HPMVEC) with SU5416 and analyzed these cells utilizing quantitative-PCR, immunofluorescent staining and flow cytometry analysis. In vitro studies in HPMVEC demonstrated that SU5416 suppressed PGI₂S gene expression while potently inducing COX-2, VEGF, and TGF-ß₁ expression; and caused transdifferentiation of mature vascular endothelial cells (defined by Dil-ac-LDL, Lectin and Factor VIII) to SM-like (as defined by expression of -SM actin) "transitional" cells, coexpressing both endothelial and SM markers. SU5416 expanded the number of CD34 and/or c-kit positive cells and caused transdifferentiation of CD34 positive cells but not negative cells. In conclusion, our data show that SU5416 generated a selection pressure that killed some EC and expanded progenitor-like cells to transdifferentiate to SM-like and neuronal-like cells.—Sakao, S., Taraseviciene-Stewart, L., Cool, C. D., Tada, Y., Kasahara, Y., Kurosu, K., Tanabe, N., Takiguchi, Y., Tatsumi, K., Kuriyama, T., and Voelkel, N. F. VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34⁺ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells.

Key Words: pulmonary hypertension • human pulmonary microvascular endothelial cells

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